Aminopyridine-containing thiourea inhibitors of herpes viruses

ABSTRACT

Compounds of the formula                    
     wherein 
     A is heteroaryl; 
     R 9 -R 12  are independently hydrogen, alkyl of 1 to 4 carbon atoms, perhaloalkyl of 1 to 4 carbon atoms, halogen, alkoxy of 1 to 4 carbon atoms, or cyano, or R 9  and R 10  or R 11  and R 12  may be taken together to form aryl of 5 to 7 carbon atoms; 
     W is O, NR 6 , or is absent; 
     G is aryl or heteroaryl; and 
     X is a bond X is a bond, —NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, thioalkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, or (CH)J; and 
     J is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl or benzyl; and 
     n is an integer from 1 to 6; or a pharmaceutical acceptable salt thereof, useful in the treatment of diseases associated with herpes viruses including human cytomegalovirus, herpes simplex viruses, Epstein-Barr virus, varicella-zoster virus, human herpesviruses-6 and -7, and Kaposi herpesvirus.

This application claims the benefit of U.S. Provisional Application Nos.60/150,698, 60/155,240, 60/228,808, 60/228,805, 60/155,192, 60/150,692,60/228,809 each of which was filed Dec. 9, 1998. These applications areherein incorporated by reference in their entireties.

BACKGROUND OF THE INVENTION

Eight viruses have been identified which are members of the familyHerpesviridae (reviewed in Roizman, B. 1996. Herpesviridae, p.2221-2230. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), FieldsVirology, 3rd ed. Lippincott-Raven Publishers, Philadelphia, Pa.). Eachmember of this family is characterized by an enveloped virus containingproteinaceous tegument and nucleocapsid, the latter of which houses theviruses' relatively large double-stranded DNA genome (i.e. approximately80-250 kilobases). Members of the human alphaherpesvirus subfamily areneurotropic and include herpes simplex virus type 1 (HSV-1) and type 2(HSV-2), and varicella-zoster virus (VZV). The human betaherpesvirusesare cytomegalovirus (HCMV), human herpesvirus 6 (HHV-6) and humanherpesvirus 7 (HHV-7). The gammaherpesviruses are lymphotropic andinclude Epstein-Barr virus (EBV) and Kaposi's herpesvirus (HHV-8). Eachof these herpesviruses is causally-related to human disease, includingherpes labialis and herpes genitalis (HSV-1 and HSV-2 [Whitley, R. J.1996. Herpes Simplex Viruses, p. 2297-2342. In B. N. Fields, D. M.Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-RavenPublishers, Philadelphia, Pa.]); chicken pox and shingles (VZV [Arvin,A. 1996. Varicella-Zoster Virus, p. 2547-2585. In B. N. Fields, D. M.Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-RavenPublishers, Philadelphia, Pa.]); infectious mononucleosis (EBV[Rickinson, A. B. and Kieff, E. 1996. Epstein-Barr Virus, p. 2397-2446.In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology,3rd ed. Lippincott-Raven Publishers, Philadelphia, Pa.]); pneumonia andretinitis (HCMV [(Britt, W. J., and Alford, C. A. 1996. Cytomegalovirus,p. 2493-2523. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.),Fields Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia,Pa.]); exanthem subitum (HHV-6 [(Pellet, P. E, and Black, J. B. 1996.Human Herpesvirus 6, p. 2587-2608. In B. N. Fields, D. M. Knipe, and P.M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers,Philadelphia, Pa.] and HHV-7 [Frenkel, N., and Roffman, E. 1996. HumanHerpesvirus 7, p. 2609-2622. In B. N. Fields, D. M. Knipe, and P. M.Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers,Philadelphia, Pa.]); and Kaposi's sarcoma (HHV-8 [Neipel, F., Albrecht,J. C., and Fleckenstein, B. 1997. Cell-homologous genes in the Kaposi'ssarcoma-associated rhadinovirus human herpesvirus 8: determinants of itspathogenicity? J. Virol. 71:4187-92, 1997]). HCMV is considered in moredetail below. Following the primary infection, herpesviruses establishlatency within the infected individual and remain there for theremainder of his/her life. Periodic reactivation of latent virus isclinically relevant. In the case of HSV, reactivated virus can betransmitted to infants during birth, causing either skin or eyeinfection, central nervous system infection, or disseminated infection(i.e. multiple organs or systems). Shingles is the clinicalmanifestation of VZV reactivation. Treatment of HSV and VZV is generallywith antiviral drugs such as acyclovir (Glaxo Wellcome), ganciclovir(Roche) and foscarnet (Asta) which target viral encoded DNA polymerase.

HCMV is a ubiquitous opportunistic pathogen infecting 50-90% of theadult population (Britt, W. J., and Alford, C. A. 1996. Cytomegalovirus,p. 2493-2523. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.),Fields Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia,Pa.). Primary infection with HCMV is usually asymptomatic, althoughheterophile negative mononucleosis has been observed. The virus ishorizontally transmitted by sexual contact, breast milk, and saliva.Intrauterine transmission of HCMV from the pregnant mother to the fetusoccurs and is often the cause of serious clinical consequences. HCMVremains in a latent state within the infected person for the remainderof his/her life. Cell-mediated immunity plays a central role incontrolling reactivation from latency. Impaired cellular immunity leadsto reactivation of latent HCMV in seropositive persons.

HCMV disease is associated with deficient or immature cellular immunity.There are 3 major categories of persons with HCMV disease (reviewed byBritt and Alford, 1996). (1) In immunocompromised (AIDS) patients, HCMVis one of the two most common pathogens causing clinical disease (theother is Pneumocystis). The most common manifestation of HCMV in AIDS isretinitis, although infection of other organs including the adrenalglands, lungs, GI tract, and central nervous system are also reportedfrequently. 90% of AIDs patients have active HCMV infection; 25-40%(˜85,000 patients in the United States) have life- or sight-threateningHCMV disease. HCMV is the cause of death in 10% of persons with AIDs.(2) Due to immune system suppression to reduce the risk of graftrejection, HCMV reactivation or reinfection is common amongst kidney,liver, heart, and allogeneic bone marrow transplant patients. Pneumoniais the most common HCMV disease in these patients, occurring in up to70% of these transplant patients. (3) Congenital infection due to HCMVoccurs in 1% of all births, about 40K per year. Up to 25% of theseinfants are symptomatic for HCMV disease between ages 0-3 years. HCMVdisease is progressive, causing mental retardation and neurologicalabnormalities, in children. Recent studies suggest that treatment withanti-HCMV drugs may reduce morbidity in these children.

Several antiviral drugs are currently being marketed (Bron, D., R.Snoeck, and L. Lagneaux. 1996. New insights into the pathogenesis andtreatment of cytomegalovirus. Exp. Opin. Invest. Drugs 5:337-344;Crumpacker, C. 1996. Ganciclovir. New Eng. J. Med. 335:721-729; Sachs,S., and F. Alrabiah. 1996. Novel herpes treatments: a review. Exp. Opin.Invest. Drugs 5:169-183). These include: ganciclovir (Roche), anucleoside analog with hemopoietic cell toxicity; foscarnet (Astra), apyrophosphate analog with nephrotoxicity; and cidofovir, Gilead), anucleoside phosphonate with acute nephrotoxicity. Each of these drugstarget the viral-encoded DNA polymerase, are typically administeredintravenously due to their low bioavailability, and, as noted above, arethe source of significant toxicity. Ganciclovir-resistant mutants whicharise clinically are often cross-resistant with cidofovir. Hence, thereis a need for safer (i.e. less toxic), orally bioavailable anti-viraldrugs which are directed against novel viral targets.

Phenyl thioureas are disclosed for use in a variety of pharmaceuticalapplications. Armistead, et al., WO 97/40028, teaches phenyl ureas andthioureas as inhibitors of the inosine monophosphate dehydrogenase(IMPDH) enzyme which is taught to play a role in viral replicationdiseases such herpes.

Widdowson, et al., WO 96/25157, teaches phenyl urea and thioureacompounds of the below formula for treating diseases mediated by thechemokine, interleukin-8.

Morin, Jr., et al., U.S. Pat. No. 5,593,993 teaches certain phenylthiourea compounds for treatment of AIDs and the inhibition of thereplication of HIV and related viruses.

Therefore, it is an object of this invention to provide compounds, andpharmaceutically acceptable salts thereof, to inhibit and/or treatdiseases associated with herpes viruses including human cytomegalovirus,herpes simplex viruses, Epstein-Barr virus, varicella-zoster virus,human herpesviruses-6 and -7, and Kaposi herpesvirus.

DESCRIPTION OF THE INVENTION

In accordance with the present invention are provided compounds havingthe formula:

wherein

A is heteroaryl;

R₉-R₁₂ are independently hydrogen, alkyl of 1 to 4 carbon atoms,perhaloalkyl of 1 to 4 carbon atoms, halogen, alkoxy of 1 to 4 carbonatoms, or cyano, or R₉ and R₁₀ or R₁₁ and R₁₂ may be taken together toform aryl of 5 to 7 carbon atoms;

W is O, NR₆, or is absent;

G is aryl or heteroaryl;

X is a bond, —NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbonatoms, alkoxy of 1 to 6 carbon atoms, thioalkyl of 1 to 6 carbon atoms,alkylamino of 1 to 6 carbon atoms, or (CH)J; and

J is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms,phenyl or benzyl; and

n is an integer from 1 to 6; or a pharmaceutically acceptable saltthereof.

In some preferred embodiments of the present invention A is a 5 or 10membered mono or bicyclic heteroaryl having 1 or 2 heteroatoms. Morepreferably, A is pyridyl, furyl, imidazolyl, pyrrolyl, thienyl, orindanyl. Still more preferably, A is 3-pyridyl.

In some preferred embodiments of the present invention A is substitutedwith one or more substitutents selected from alkyl of 1 to 6 carbonatoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms,perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms,heterocycloalkyl of 3 to 10 carbon members, aryl, heteroaryl, halogen,—CN, —NO₂, —CO₂R₆, —COR₆, —OR₆, —SR₆, —SOR₆, —SO₂R₆, —CONR₇R₈,—NR₆N(R₇R₈), —N(R₇R₈) or W—Y—(CH₂)_(n)—Z wherein R₆ and R₇ areindependently hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1to 6 carbon atoms, or aryl; R₈ is hydrogen, alkyl of 1 to 6 carbonatoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbonatoms, heterocycloalkyl of 3 to 10 members, aryl or heteroaryl, or

R₇ and R₈, taken together may form a 3 to 7 membered heterocycloalkyl;

W is O, NR₆, or is absent;

Y is —(CO)— or —(CO₂)—, or is absent;

Z is alkyl of 1 to 4 carbon atoms, —CN, —CO₂R₆, COR₆, —CONR₇R₈, —OCOR₆,—NR₆COR₇, —OCONR₆, —OR₆, —SR₆, —SOR₆, —SO₂R₆, SR₆N(R₇R₈), —N(R₇R₈) orphenyl; and n is 1 to 6.

In still more preferred embodiments A is substituted with one or moresubstitutents selected from halogen or alkyl of 1-6 carbon atoms.

In some embodiments of the present invention, at least 1 of R₉-R₁₂ isnot hydrogen. Preferably when one of R₉-R₁₂ is not hydrogen, one or moreof R₉-R₁₂ are selected from halogen, methyl, methoxy, and cyano. Morepreferably each of R₉-R₁₂ is hydrogen.

G is preferably a 5 or 6 membered heteroaryl having 1 or 2 heteroatoms.More preferably, G is furyl or thiadiazole and in still more preferredembodiments, G is 1,2,3 thiadiazolyl or 2-furyl. Alternatively, G may bealkyl of 1 to 6 carbon atoms which optionally may be substituted,preferably by a halogen.

X is preferably a bond or straight chain lower alkyl group. When X is alower alkyl group it is preferred that X is methyl or ethyl.

Preferred compounds of the present invention are the following compoundswhich include pharmaceutically acceptable salts thereof.

Furan-2-carboxylic acid [4-(3-pyridin-2-yl-thioureido)-phenyl]-amide;

Furan-2-carboxylic acid [4-(3-pyridin-4-yl-thioureido)-phenyl]-amide;

Furan-2-carboxylic acid [4-(3-pyridin-3-yl-thioureido)-phenyl]-amide;

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(6-chloro-pyridin-3-yl)-thioureido]-phenyl}-amide;

Furan-2-carboxylic acid [4-(3-pyrimidin-4-yl-thioureido)-phenyl]-amide;

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(5-chloro-pyridin-3-yl)-thioureido]-phenyl}-amide;

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(5-bromo-pyridin-3-yl)-thioureido]-phenyl}-amide;

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(1-tert-butyl-1H-imidazol-2-yl)-thioureido]-phenyl}-amide;

Furan-2-carboxylic acid {4-[3-(1-tert-butyl-1H-imidazol-2-yl)-thioureido]-phenyl}-amide;

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(5-trifluoromethyl-pyridin-3-yl)-thioureido]-phenyl}-amide;

Furan-2-carboxylic acid[4-(3-pyridin-3-ylmethyl-thioureido)-phenyl]-amide;

[1,2,3]Thiadiazole-4-carboxylic acid[4-(3-pyridin-3-ylmethyl-thioureido)-phenyl]-amide;

[1,2,3]Thiadiazole-4-carboxylic acid[4-(3-indan-1-yl-thioureido)-phenyl]-amide;

Furan-2-carboxylic acid[4-(3-pyridin-4-ylmethyl-thioureido)-phenyl]-amide;

[1,2,3]Thiadiazole-4-carboxylic acid[4-(3-pyridin-4-ylmethyl-thioureido)-phenyl]-amide;

2-Fluoro-N-[4-(3-pyridin-3-yl-thioureido)-phenyl]-benzamide;

2-Fluoro-N-[4-(3-pyridin-2-yl-thioureido)-phenyl]-benzamide;

2-Fluoro-N-[4-(3-pyridin-4-yl-thioureido)-phenyl]-benzamide;

2-Fluoro-N-[4-(3-pyridin-3-ylmethyl-thioureido)-phenyl]-benzamide;

2-Fluoro-N-{4-[3-(1H-indazol-5-yl)-thioureido]-phenyl}-benzamide;

N-{4-[3-(1-tert-Butyl-1H-imidazol-2-yl)-thioureido]-phenyl}-2-fluoro-benzamide;

2-Fluoro-N-[4-(3-pyridin-4-ylmethyl-thioureido)-phenyl]-benzamide;

2-Fluoro-N-{4-[3-(1-furan-2-yl-ethyl)-thioureido]-phenyl}-benzamide;

2-Fluoro-N-{4-[3-(1-pyridin-4-yl-ethyl)-thioureido]-phenyl}-benzamide;

2-Fluoro-N-(4-{3-[1-(1-methyl-1H-pyrrol-2-yl)-ethyl]-thioureido}-phenyl)-benzamide;and

2-Fluoro-N-{4-[3-(1-thiophen-3-yl-ethyl)-thioureido]-phenyl}-benzamide.

Alkyl as used herein refers to straight or branched chain lower alkyl of1 to 6 carbon atoms. Exemplary alkyl groups include methyl, ethyl,propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.

Alkenyl as used herein refers to straight or branched chain lower alkylof 2 to 6 carbon atoms containing at least one carbon-carbon doublebond. Alkenyl includes vinyl groups.

Alkynyl as used herein refers to straight or branched chain lower alkylof 2 to 6 carbon atoms containing at least one carbon-carbon triplebond.

Alkyl, alkenyl and alkynyl groups of the present invention may besubstituted or unsubstituted.

Cycloalkyl refers to a saturated mono or bicyclic ring system of 3 to 10carbon atoms. Exemplary cycloalkyl groups include cyclopentyl,cyclohexyl and cycloheptyl. Cycloalkyl groups of the present inventionmay be substituted or unsubstituted.

Heterocycloalkyl refers to a saturated mono or bicyclic ring system of 3to 10 members having 1 to 3 heteroatoms selected from N, S and 0,including, but not limited to aziridinyl, azetidinyl, imidazolidinyl,morpholinyl, thiomorpholinyl, piperazinyl, pyrazolidinyl, piperidinyl,and pyrrolidinyl. Heterocycloalkyl groups of the present invention maybe substituted or unsubstituted.

Aryl, as used herein refers to an aromatic mono or bicyclic ring of 5 to10 carbon atoms. Exemplary aryl groups include phenyl, naphthyl, andbiphenyl. Aryl groups of the present invention may be substituted orunsubstituted.

Heteroaryl as used herein refers to an aromatic mono or bicyclic ring of5 to 10 members having 1 to 3 heteroatoms selected from N, S or Oincluding, but not limited to thiazolyl, thiadiazolyl, oxazolyl, furyl,indolyl, benzothiazolyl, benzotriazolyl, benzodioxyl, indazolyl, andbenzofuryl. Preferred heteroaryls include quinolyl, isoquinolyl,napthalenyl, benzofuranyl, benzothienyl, indolyl, pyridyl, pyrazinyl,thienyl, furyl, pyrrolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl,pyrazolyl, triazolyl, thiadiazolyl, and imidazolyl. Heteroaryl groups ofthe present invention may be substituted or unsubstituted.

Perhaloalkyl refers to an alkyl group of 1 to 6 carbon atoms in whichthree or more hydrogens are substituted with halogen.

Phenyl as used herein refers to a 6 membered aromatic ring.

Halogen, as used herein refers to chlorine, bromine, iodine andfluorine.

Unless otherwise limited substitutents are unsubstituted and may includealkyl of 1 to 6 carbon atoms, cycloalkyl of 1 to 6 carbon atoms,heterocycloalkyl of 1 to 6 members, perhaloalkyl of 1 to 6 carbon atoms,alkylamino, dialkylamino, aryl or heteroaryl.

Carbon number refers to the number of carbons in the carbon backbone anddoes not include carbon atoms occurring in substituents such as an alkylor alkoxy substituents.

Where terms are used in combination, the definition for each individualpart of the combination applies unless defined otherwise. For instance,alkylcycloalkyl is an alkyl-cycloalkyl group in which alkyl andcycloalkyl are as previously described.

Pharmaceutically acceptable salts are the acid addition salts which canbe formed from a compound of the above general formula and apharmaceutically acceptable acid such as phosphoric, sulfuric,hydrochloric; hydrobromic, citric, maleic, succinic, fumaric, acetic,lactic, nitric, sulfonic, p-toluene sulfonic, methane sulfonic acid, andthe like.

The compounds of this invention contain a chiral center, providing forvarious seteroisomeric forms of the compounds such as racemic mixturesas well as the individual optical isomers. In some preferred embodimentsof the present invention the compounds of the present invention aresubstantially pure optical isomers. By substantially pure is meant thecomposition contains greater than 75% of the desired isomer and mayinclude no more than 25% of the undesired isomer. In more preferredembodiments the pure optical isomer is greater than 90% of the desiredisomer. In some preferred embodiments, when the target is VZV, the (S)isomer is preferred. The individual isomers can be prepared directly orby asymmetric or stereospecific synthesis or by conventional separationof optical isomers from the racemic mixture.

Compounds of the present invention may be prepared by those skilled inthe art of organic synthesis employing methods described below whichutilize readily available reagents and starting materials unlessotherwise described. Compounds of the present invention are thusprepared in accordance with the following schemes.

The novel compounds of the present invention are prepared according tothe following reaction schemes. Similarly, reaction of appropriatelysubstituted isothiocyanates 4, wherein the substitutents of A, and X aredescribed as above with appropriately substituted anilines 5, whereinthe substituents R₉-R₁₂ and G are described above, in a convenientsolvent such as those listed above affords the desired thioureas 1.

Methods 31 and 34

Alternatively, appropriately substituted thioureas 1 can be prepared asdescribed by Methods 32 and 33 by reacting amines 2 and 5 in thepresence of either one molar equivalent of 1,1′-thiocarbonyl diimidazolein an appropriate solvent such as dichloro-methane and tetrahydrofuranor mixtures thereof or one molar equivalent of1,1′-thiocarbonyl-di-(1,2,4)-triazole in an appropriate solvent such asdichloromethane and tetrahydrofuran or mixtures thereof at roomtemperature.

In certain instances, subsequent chemical modification of the finalthioureas 1 was required. These methods, Methods 35-39, are summarizedbelow.

Thioureas 1 wherein A comprises at least one substituent which is1-hydroxyethoxy or carboxy-methoxy, R₉-R₁₂ and G are defined as aboveand X equals a bond, may be prepared from the corresponding alkyl estersby alkaline hydrolysis with aqueous sodium or potassium hydroxide in asuitable solvent such as methanol, tetrahydrofuran or mixtures thereofat room temperature in accordance with Methods 35 and 36.

Thioureas 1 wherein A comprisese at least one substituent which is 1-acyloxyethoxy or methansulfonoxyethoxy, R₉-R₁₂ and G are defined asabove and X equals a bond, may be prepared from the corresponding1-hydroxyethoxy derivative by acylation with appropriate acylatingagents such as benzoic acid chloride or methanesulfonic acid chloride inthe presence of a suitable tertiary amine base such as triethylamine ordiisopropylethylamine in a suitable solvent such as dichloromethane orthe like at room temperature in accordance with Methods 37 and 38.

Thioureas 1 wherein A comprises at least one substituent which is1-aminoethoxy, R₉-R₁₂ and G are defined as above and X equals a bond,may be prepared from the corresponding 1-methanesulfonoxy-ethoxyderivative by reaction with an appropriate secondary amine such asdimethylamine in a suitable solvent mixture such as tetrahydrofuran andwater or the like at room temperature in accordance with Method 39.

Thioureas 1 wherein A comprises at least one substituent which is1-aminoalkyl, R₉-R₁₂ and G are defined as above and X equals a bond, maybe prepared from the corresponding 1-azidoalkyl derivative by reactionwith stannous chloride in a suitable solvent such as methanol, ethanolor the like at room temperature in accordance with Method 40.

The intermediate isothiocyanates 3 and 4 shown above in Methods 31 and34 are prepared in accordance with Method 41 (below) essentiallyaccording to the procedures of Staab, H. A. and Walther, G. JustusLiebigs Ann. Chem. 657, 104 (1962)) by reacting appropriatelysubstituted amines 5 or 2, respectively, X is defined above with onemolar equivalent of 1,1′-thiocarbonyldiimidazole in an appropriatesolvent such as dichloromethane and tetrahydrofuran or mixtures thereof.

The intermediates 2 and 5 may be prepared according to the followingprotocols:

According to Methods 1A-1G, amines 2, wherein A is defined above and Xis defined above and amines 5, wherein R₉-R₁₂ are defined above, may beprepared by reduction of the appropriately substituted nitrobenzenes andcorresponding heteroaryls according to a variety of procedures known tothose skilled in the art and described in R. J. Lindsay, ComprehensiveOrganic Chemistry (ed. Sutherland), Volume 2, Chapter 6.3.1, AromaticAmines, 1979. Such procedures include the reduction of nitrobenzenes toform anilines upon exposure to:

a) iron powder and a strong acid, such as hydrochloric acid (Methods 1A)either neat or in alcohol solvent such as methanol or ethanol, attemperatures ranging from room temperature to the refluxing temperatureof the solvent, or;

b) iron powder and glacial acetic acid (Method 1B), either neat or inalcohol solvent such as methanol or ethanol, at temperatures rangingfrom room temperature to the refluxing temperature of the solvent, or;

c) iron powder and aqueous ammonium chloride (Method 1C), either neat orin alcohol solvent such as methanol or ethanol, at temperatures rangingfrom room temperature to the refluxing temperature of the solvent, or;

d) tin and a strong mineral acid, such as hydrochloric acid (Method 1D),either neat or in alcohol solvent such as methanol or ethanol, attemperatures ranging from room temperature to the refluxing temperatureof the solvent, or;

e) when substitutents of A and R₉-R₁₂ are selected from Cl, Br, I,—(OSO₂)—CF₃, or —(OSO₂)-1-(4-methylphenyl), by catalytic reduction suchas with hydrogen and palladium on carbon (Method 1E) in an appropriatesolvent such as methanol, ethanol, or ethyl acetate, under one or moreatmospheres of pressure or;

f) when substituents of A and R₉-R₁₂ are selected from Cl, Br, I,—(OSO₂)—CF₃, or —(OSO₂)-1-(4-methylphenyl), by catalytic reduction suchas with cyclohexene and palladium on carbon (Method IF) in anappropriate solvent such as methanol or ethanol, at temperatures rangingfrom room temperature to the refluxing temperature of the solvent, or;

g) aqueous sodium hydrosulfite in alcohol solvent at temperaturesranging from room temperature to the refluxing temperature of thesolvent (Method 1G).

Alternatively, according to Methods 3A-3C, amines 2, wherein A isdefined above and X is defined above and anilines 5, wherein R₉-R₁₂ aredefined above, may be prepared by the cleavage of the anilinenitrogen-carbon bond of amide and carbamate derivatives of theseanilines according to a variety of procedures known to those skilled inthe art and described in Greene, Protective Groups in Organic Synthesisvolume 2, Chapter 7, 1991, and references therein. Such proceduresinclude:

a) the exposure of appropriately substitutedarylamino-tert-butyl-carbamates to a strong acid such as trifluoroaceticacid (Method 3A)either neat or in an appropriate solvent such asdichloromethane at temperatures between 0° C. and room temperature, or;

b) the exposure of appropriately substitutedarylamino-(2-trimethylsilylethyl)-carbamates to a fluoride ion sourcesuch as tetrabutylammonium fluoride or potassium fluoride (Method 3B) inaqueous acetonitrile or tetrahydrofuran or mixtures thereof attemperatures ranging from room temperature to the reflux temperature ofthe solvent, or;

c) the exposure of appropriately substitutedarylamino-trifluoroacetamides to a strong base such as sodium orpotassium hydroxide or sodium or potassium carbonate in an alcoholsolvent such as methanol or ethanol (Method 3C) at temperatures rangingfrom room temperature to the reflux temperature of the solvent.

Alternatively, according to Method 11, amines 2, wherein A is definedabove, and X equals a bond and at least one substituent of A is vinyl,may be prepared by the palladium catalyzed coupling of a vinyltrialkyltin reagent, such as tributylvinyltin, with an appropriatelysubstituted bromo- or iodo-aniline, for example 3-chloro-4-iodo-aniline,employing a palladium catalyst, such astris(dibenzylidineacetone)-bipalladium, and a ligand, such astriphenylarsine, in a suitable solvent such as tetrahydrofuran orN-methylpyrrolidinone, at temperatures ranging from room temperature tothe reflux temperature of the solvent, essentially according to theprocedures of V. Farina and G. P. Roth in Advances in Metal-OrganicChemistry, Vol. 5, 1-53, 1996 and references therein.

Alternatively, according to Method 42, amines 2, wherein A is definedabove and X is defined above and at least one substituent of A isdefined as dialkylamino, may be prepared by the palladium catalyzedamination of an appropriately substituted 3- or 5-bromo- oriodo-aniline, by secondary amines under conditions which employ apalladium catalyst, such as bis(dibenzylidineacetone)palladium, and aligand, such as tri-o-tolylphosphine, and at least two molar equivalentsof a strong base, such as lithium bis-(trimethylsilyl)amide in a sealedtube, in a suitable solvent such as tetrahydrofuran or toluene, attemperatures ranging from room temperature to 100° C., essentiallyaccording to the procedures of J. F. Hartwig and J. Louie TetrahedronLetters 36 (21), 3609 (1995).

Alternatively, according to Method 43, amines 2, wherein A is definedabove and X is defined above and at least one substituent of A isdefined as alkyl, may be prepared by the palladium catalyzed alkylationof an appropriately substituted 3- or 5-bromo-or iodo-aniline, byalkenes under condiditons which employ a palladium catalyst such as[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)chloride-dichloromethane complex and in the presence of9-borabicyclo[3.3.1] nonane and a suitable base such as aqueous sodiumhydroxide in a suitable solvent such as tetrahydrofuran or the like attemperatures ranging from room temperature to the reflux temperature ofthe solvent.

The acyl and carbamoyl amine derivatives utilized as starting materialsin Methods 3A-3C may be prepared by the derivatization of thecorresponding amines as described in Methods 2A-2G according to avariety of procedures known to those skilled in the art and described inGreene, Protective Groups in Organic Synthesis volume 2, Chapter 7,1991, and references therein. Such procedures include:

a) the reaction of an appropriately substituted amine withdi-tert-butyl-dicarbonate (Method 2A) in the presence or absence of oneor more molar equivalents of a tertiary amine such as triethylamine orN,N-diisopropylethylamine in a suitable solvent such as acetone,tetrahydrofuran, dimethylformamide, dichloromethane, and the like, attemperatures ranging from room temperature to the reflux temperature ofthe solvent to produce the corresponding arylamino-tert-butyl-carbamate,or;

b) the reaction of an appropriately substituted aniline with1-[2-(trimethylsilyl)ethoxycarbonyl-oxy]benzotriazole (Method 2B) in thepresence of a tertiary amine such as triethylamine ordiisopropylethylamine in a suitable solvent such as dimethylformamide atroom temperature to produce the correspondingheteroarylamino-(2-trimethylsilylethyl)-carbamate, or;

c) the reaction of an appropriately substituted aniline with acarboxylic acid chloride or acid anhydride (Method 2C) either neat or inan appropriate solvent such as tetrahydrofuran, dimethylformamide,dichloromethane, pyridine and the like, in the presence of one or moremolar equivalents of a teriary amine base such as triethylamine orN,N-diisopropylethyl-amine to produce the corresponding arylaminoamide,or;

d) the reaction of an apptopriately substituted nitro aniline with acarboxylic acid chloride (Method 2D) in the absence of one or more molarequivalents of a teriary amine base such as triethylamine orN,N-diisopropylethylamine either neat or in an appropriate solvent suchas tetrahydrofuran, 1,4-dioxane and the like at temperatures rangingfrom room temperature to the reflux temperature of the solvent toproduce the corresponding nitro arylaminoamide, or;

e) the reaction of an appropriately substituted aniline with acarboxylic acid (Method 2E) in the presence of a coupling agent such asbenzotriazole-1-yloxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate,2-(1H-benzotriazole-1-yloxy)-1,1,3,3-tetra-methyluroniumhexafluorophosphate, dicyclohexyl carbodiimide and the like and in thepresence of a tertiary amine such as triethylamine ordiisopropylethylamine in a suitable solvent such as diichloromethane,dimethylformamide and the like, at room temperature to produce thecorresponding arylaminoamide, or;

f) the reaction of an appropriately protected aniline such as anheteroarylamino-tert-butyl-carbamate or the like in which at least onesubstituent of A and R₁-R₁₂ is defined as —W—Y—(CH₂)_(n)—Z wherein W, Y,and Z are defined as above, with a carboxylic acid anhydride (Method 2F)in the presence of a suitable base such as pyridine in an appropriatesuch as dichloromethane, dimethylformamide or the like at temperaturesranging from 0° C. to room temperature to produce the correspondingcarboxylic acid ester, or;

g) the reaction of an appropriately substituted aniline in which atleast one substituent of A is defined as hydroxyl withdi-tert-butyl-dicarbonate (Method 2G) in the absence of one or moremolar equivalents of a tertiary amine such as triethylamine orN,N-diisopropylethylamine in a suitable solvent such as acetone,tetrahydrofuran, dimethylformamide, dichloromethane, and the like, attemperatures ranging from room temperature to the reflux temperature ofthe solvent to produce the correspondingheteroarylamino-tert-butyl-carbamate.

Nitrobenzene intermediates that are ultimately converted to amines 2 and5 by methods shown above in Methods 1A-1G may be prepared in accordancewith Methods 4A, 4C, 4E-4F.

Referring to Methods 4A, 4C, and 4E-4H, the nitrobenzene intermediateswhich are ultimately converted into amines 2, where A comprisessubstituent defined as alkoxy, thioalkoxy, alkylsulfenyl, alkylsulfinyl,and dialkylamino may be prepared by the nucleophilic displacement ofappropriately substituted 2-, 4-, and/or 6-fluoro-, chloro-, bromo-,iodo-, trifluoromethylsulfonyl-, or (4-methylphenyl)sulfonyl-substitutednitrobenzenes or corresponding heteroaryls by methods which include thefollowing:

a) reaction of alcohols with appropriately substituted 2- or 4- halo- orsulfonate esters of nitrobenzenes, benzonitriles or correspondingheteroaryls (Method 4A) either neat or in an appropriate solvent such astetrahydrofuran, dioxane, acetonitrile, N,N-dimethylformamide ordimethylsulfoxide in the presence or absence of one or more molarequivalents of a base such as sodium carbonate, potassium carbonate,sodium hydroxide, potassium hydroxide, sodium hydride, potassiumhydride, or the like, at temperatures ranging from room temperature tothe reflux temperature of the solvent;

b) reactions of preformed sodium, lithium, or potassium phenoxides withappropriately substituted 2- or 4- halo- or sulfonate esters ofnitrobenzenes, benzonitriles or corresponding heteroaryls (Method 4H)either neat or in an appropriate solvent such as tetrahydrofuran,dioxane, acetonitrile, N,N-dimethylformamide or dimethylsulfoxide, attemperatures ranging from room temperature to the reflux temperature ofthe solvent, or;

c) reaction of ammonia, primary or secondary amines with appropriatelysubstituted 2- or 4-halo- or sulfonate esters of nitrobenzenes,benzonitriles or corresponding heteroaryls (Methods 4C,F) either neat orin an appropriate solvent such as tetrahydrofuran, dioxane,acetonitrile, N,N-dimethyl-formamide or dimethylsulfoxide, attemperatures ranging from room temperature to the reflux temperature ofthe solvent;

d) reaction of preformed sodium, lithium, or potassium salts of amineswith appropriately substituted 2- or 4- halo- or sulfonate esters ofnitrobenzenes or benzonitriles (Method 4G) in an appropriate solventsuch as tetrahydrofuran at temperatures ranging from 0C to the refluxtemperature of the solvent, or;

e) reaction of sodium sulfide with appropriately substituted 2- or 4-halo- or sulfonate esters of nitrobenzenes or benzonitriles either neator in an appropriate solvent such as tetrahydro-furan, dioxane,acetonitrile, N,N-dimethylformamide or dimethylsulfoxide, attemperatures ranging from room temperature to the reflux temperature ofthe solvent, followed by the addition of an alkyl halide directly to thereaction mixture (Method 4E).

Alternatively, referring to Methods 5C and 6, the nitrobenzeneintermediates and corresponding heteroaryls which are ultimatelyconverted into amines 2, wherein at least one substitutent of A isdefined as alkoxy may be prepared from the corresponding substitutedhydroxy-nitrobenzenes and corresponding heteroaryls by methods whichinclude the following:

a) reaction of the hydroxy-nitrobenzene with an alkyl halide or dialkylsulfonate ester (Method 5C) in the presence of a base, such as potassiumcarbonate, sodium carbonate, potassium hydroxide, sodium hydroxide,potassium hydride, or sodium hydride, in an appropriate solvent such asacetone, N,N-dimethylformamide, tetrahydrofuran or dimethylsulfoxide attemperatures ranging from room temperature to the reflux temperature ofthe solvent, or;

b) reaction of the hydroxy-nitrobenzene or corresponding heteroaryl withan alkyl alcohol, triphenylphosphine, and a dialkylazadicarboxylatereagent (Method 6), such as diethylazodicarboxylate, in an anhydrousaprotic solvent such as diethyl ether or tetrahydrofuran at temperaturesranging from 0° C. to the reflux temperature of the solvent, essentiallyaccording to methods described in Mitsunobu, O, Synthesis 1981, 1 andreferences therein.

In addition, referring to Method 5A and 5E, the carbamoyl aminederivatives utilized as starting materials in Methods 3A-3C which areultimately converted into amines 2, wherein at least one substituent ofA is defined as alkoxy may be prepared the corresponding substitutedhydroxy aryl- or heteroarylamino-tert-butyl-carbamate by reaction withalkyl halides, trifluormethane-sulfonates, 4-methylbenzenesulfonates,dialkylsulfonate, ethylene carbonate and the like in the presence of asuitable base such as potassium carbonate in an appropriate solvent suchas acetone, toluene, or N,N-dimethyl-formamide at temperatures rangingfrom room temperature to the reflux temperature of the solvent.

Alternatively, referring to Methods 7A-G, the nitrobenzene andcorresponding heteroaryls which are ultimately converted into amines 2,comprising at least one alkoxy at least one halogen, and X equals abond, may be prepared by standard halogenation reactions which includethe following:

a) reaction of a 2- or 4- hydroxy-nitrobenzene or correspondingheteroaryl with aqueous sodium hypochlorite (Methods 7A and 7B), at roomtemperature or;

b) reaction of a 2-hydroxy-4-methoxy or 2,4-dimethoxynitrobenzene orcorresponding heteroaryl (Method 7C and 7D) with bromine in suitablesolvent such as chloroform, dichlormethane, glacial acetic acid or thelike in the presence or the absence of silver trifluoroacetate at roomtemperature, or;

c) reaction of a 2,4-dimethoxynitrobenzene or corresponding heteroaryl(Method 7E) with benzyltrimethylammonium dichloroiodate in the presenceof anhydrous zinc chloride in a suitable solvent such as glacial aceticacid, at room temperature or;

d) reaction of a 2-hydroxy-4-methoxynitrobenzene or correspondingheteroaryl (Method 7F) with benzyltrimethyl-ammonium dichloroiodate inthe presence of sodium bicarbonate in a suitable solvent mixture such asdichloromethane and methanol, at room temperature or;

e) reaction of a 2,4-dimethoxynitrobenzene or corresponding heteroaryl(Method 7G) with 3,5-dichloro-1-fluoropyridine triflate in a suitablesolvent such as tetrachloroethane, at a temperature ranging from roomtemperature to the reflux temperature of the solvent.

Referring to Method 8, the nitrobenzene intermediates or correspondingheteroaryl which are ultimately converted into amines 2, wherein A issubstituted by CF₃ and X equals a bond may be prepared from thecorresponding substituted 4-iodo-nitrobenzenes or correspondingheteroaryl by reaction with trimethyl(trifluoromethyl)silane in thepresence of cuprous iodide and potassium fluoride in a suitable solventsuch as N,N-dimethyl-formamide or the like at a temperature ranging fromroom temperature to the reflux temperature of the solvent in a sealedreaction vessel.

Referring to Methods 19A and 19B, the nitrobenzene intermediates whichare ultimately converted into amines 2, wherein A comprises asubstituent defined as —HNCOCH₂NR₇R₈ or —HNCOCH₂SR₆, and X equals a bondmay be prepared from the corresponding substituted4-(N-chloroacetyl)-nitroaniline by reaction with either a suitablesecondary amine such as dimethylamine, morpholine or the like in asuitable solvent such as tetrahydrofuran and/or water mixtures attemperatures ranging from room temperature to the reflux temperature ofthe solvent or by reaction with an appropriate thiol in the presence ofa suitable base such as sodium or potassium carbonate or the like in asuitable solvent such as tetrahydrofuran, 1,4-dioxane or the like attemperatures ranging from room temperature to the reflux temperature ofthe solvent.

Referring to Method 25, the nitrobenzene intermediates or correspondingheteroaryl which are ultimately converted into amines 2, wherein atleast one substituent of A is defined as triflate and X equals a bondmay be prepared from the corresponding phenol by reaction withtrifluoromethane sulfonic anhydride in the presence of a tertiary aminessuch as triethylamine or diisopropyl-ethylamine or the like in asuitable solvent such as dichloromethane at temperatures ranging from 0°C. to room temperature.

Referring to Methods 9, 9B, and 10, the carbamoyl amine derivativesutilized as starting materials in Methods 3A-3C which are ultimatelyconverted into amines 2, wherein at least one substituent A is definedas either alkylsulfenyl or alkylsulfinyl, may be prepared by reaction ofthe appropriate 4-alkylthio acylarylamino or acylheteroarylamino orcarbamoylarylamino or carbamoylheteroarylamino derivative with anappropriate oxidizing agent such as dimethyloxirane or sodium periodatein a suitable solvent mixture such as acetone and dichloromethane orwater at room temperature.

Referring to Method 12, the carbamoyl amine derivatives utilized asstarting materials in Methods 3A-3C which are ultimately converted intoamines 2, wherein a substituent of A is defined as 1-hydroxyethyl and Xequals a bond may be prepared by reacting the corresponding 4-vinylcarbamoyl aniline with sodium borohydride in the presence of mercuricacetate in a suitable solvent such as tetrahydrofuran, 1,4-dioxane orthe like and water at room temperature.

Referring to Method 13, the carbamoyl amine derivatives utilized asstarting materials in Methods 3A-3C which are ultimately converted intoamines 2, wherein a substituent of A is defined as 2-hydroxyethyl and Xequals a bond, may be prepared by reacting the corresponding 4-vinylcarbamoyl aniline with sodium borohydride in the presence of glacialacetic acid in a suitable solvent such as tetrahydrofuran, 1,4-dioxaneor the like at temperatures ranging from 0° C. to room temperature.

Referring to Method 14, the carbamoyl amine derivatives utilized asstarting materials in Methods 3A-3C which are ultimately converted intoamines 2, wherein a substituent of A is defined as 1-azidoethyl and andX is defined above, may be prepared by reacting the corresponding4-(1-hydroxyethyl) carbamoyl aniline with hydrazoic acid in the presenceof a dialkylazodicarboxylate such as diethylazodicarboxylate andtriphenylphosphine in a suitable solvent mixture such as tetrahydrofuranand dichloromethane at temperatures ranging from 0° C. to roomtemperature.

Referring to Method 15, the carbamoyl amine derivatives utilized asstarting materials in Methods 3A-3C which are ultimately converted intoamines 2, wherein a substituent of A is defined as3-dimethylaminoprop-1-ynyl and X is defined above, may be prepared byreacting the corresponding 4-iodocarbamoyl aniline with1-dimethylamino-2-propyne in a suitable tertiary amine solvent such astriethylamine or diisopropylethylamine in the presence ofbis(triphenylphosphine)palladium(II) chloride and cuprous iodide attemperatures ranging from room temperature to the reflux temperature ofthe solvent.

Referring to Method 16, the carbamoyl amine derivatives utilized asstarting materials in Methods 3A-3C which are ultimately converted intoamines 2, wherein a substituent of A is defined as3-dimethylaminoacryloyl and X equals a bond, may be prepared by reactingthe corresponding 4-(3-dimethylaminoprop-1-ynyl)carbamoyl aniline with asuitable peracid such as 3-chloroperoxybenzoic acid in a suitablesolvent mixture such as dichloromethane and methanol at temperaturesranging from 0° C. to room temperature.

Referring to Methods 17 and 18, the carbamoyl amine derivatives utilizedas starting materials in Methods 3A-3C which are ultimately convertedinto amines 2, wherein a substituent of A is defined as either4-isoxazol-5-yl or 4-(1H-pyrazol-3-yl) and X equals a bond, may beprepared by reacting the corresponding4-(3-dimethylamino-acryloyl)carbamoyl aniline with either hydroxylaminehydrochloride or hydrazine hydrate in a suitable solvent such as1,4-dioxane or ethanol and the like at room temperature.

Referring to Method 20, the carbamoyl amine derivatives utilized asstarting materials in Methods 3A-3C which are ultimately converted intoamines 2, wherein a substituent of A is defined as —HNCO₂Z, Z is definedabove and X equals a bond, may be prepared by reacting the corresponding4-aminocarbamoyl aniline with 1,1-carbonyl-di-(1,2,4)-triazole and anappropriately substituted alcohol in a suitable solvent mixture such astetrahydrofuran and dichloromethane and the like at temperatures rangingfrom room temperature to the reflux temperature of the solvent.

Referring to Methods 26 and 30, the carbamoyl amine derivatives utilizedas starting materials in Methods 3A-3C which are ultimately convertedinto amines 2, wherein at least one substituent of A is defined asdialkylamino and X is defined above may be prepared by reaction ofappropriately substituted aldehydes in the presence of either sodiumcyanoboro-hydride or hydrogen gas and 10% palladium on carbon in asuitable solvent such as water, methanol, tetrahydrofuran mixtures ortoluene or the like at room temperature.

Referring to Methods 27 and 28, amines 2 wherein at least onesubstituent of A is defined as hydroxy and X is defined above can beprepared by reaction of the corresponding ester such as acetate with anappropriate base such as sodium bicarbonate or sodium hydroxide in asuitable solvent mixture such as methanol-water mixtures at temperaturesranging from room temperature to the reflux temperature of the solvent.

Referring to Method 29, amines 2 wherein at least one substituent of Ais defined as 2-hydroxybenzamido and X is defined above can be preparedby reaction of the corresponding N-(4-aminophenyl)phthalimide withlithium borohydride in an appropriate solvent such as tetrahydrofuran,diethyl ether, or the like at room temperature.

The intermediate amines 2 wherein X equals either —CH₂— or —(CH₂)₂— canbe prepared by the following procedures:

a) reduction of an appropriately substituted benzo- phenyl- orcorresponding heteroarylacetonitrile with borane-dimethylsulfide complexin a suitable solvent such as ethylene glycol dimethyl ether,tetrahydrofuran or the like a temperatures ranging from room temperatureto the reflux temperature of the solvent. (Method 44);

17. reduction under one or more atmospheres of hydrogen in the presenceof a suitable catalyst such as 5% or 10% palladium on carbon and an acidsuch as 4-methyl-benzenesulfonic acid, hydrochloric acid or the like ina suitable solvent such as ethylene glycol monomethyl ether, ethylacetate, ethanol or the like at room temperature. (Method 50);

18. reduction with lithium aluminum hydride in a suitable solvent suchas tetrahydrofuran or diethyl ether at temperatures ranging from 0° C.to room temperature. (Method 51);

The unsaturated nitro precursors which are utilized as startingmaterials in Method 51 and are ultimately converted to amines 2 whereinX equals —(CH₂)₂— can be prepared by reaction of an appropriatelysubstituted benzaldehyde or corresponding heteroaryl with nitro-methanein the presence of ammonium acetate in a suitable solvent such as aceticacid at temperatures ranging from room temperature to the refluxtemperature of the solvent.(Method 53); The benzaldehydes orcorresponding heteroaryls, utilized as starting materials in Method 53,can be prepared by diisobutylaluminum hydride reduction of anappropriately substituted benzonitrile or corresponding heteroaryl.(Method 52) The substituted benzonitriles or corresponding heteroaryls,utilized as starting materials in Method 52, can be prepared from thecorresponding aryl or heteroaryl bromide by reaction with copper cyanidein a suitable solvent such as N,N-dimethylformamide at temperaturesranging from room temperatture to the reflux temperature of the solvent.(Method 59)

For amines 2, wherein X equals either —O(CH₂)₂NH₂ or —S(CH₂)₂NH₂, therequisite nitrile precursors may be prepared by reaction of anappropriately substituted phenol, thiophenol or corresponding heteroarylwith bromoacetonitrile in the presence of a suitable base such aspotassium carbonate in an appropriate solvent such as acetone at roomtemperature according to Method 49.

Alternatively, for amines 2, wherein X equals —(CH₂)₃—, the nitrileprecursors can be prepared essentially according to the procedure ofWilk, B. Synthetic Comm. 23, 2481 (1993), by reaction of anappropriately substituted phenethanol or corresponding heteroaryl withacetone cyanohydrin and triphenylphosphine in the presence of a suitableazodicarboxylate such as diethyl azodicarboxylate in an appropriatesolvent such as diethyl ether or tetrahydro-furan or the like attemperatures ranging from 0° C. to room temperature. (Method 54)

Alternatively, intermediate amines 2 wherein X equals —(CH(CH₃))— can beprepared by acid or base catalyzed hydrolysis of the correspondingformamide using an appropriate acid catalyst such as 6N hydrochloricacid or a suitable base catalyst such as 5N sodium or potassiumhydroxide in an appropriate solvent mixture such as water and methanolor water and ethanol at temperatures ranging from room temperature tothe reflux temperature of the solvent. (Method 46)

The formamide precursors utilized as starting materials in Method 46 andwhich are ultimately converted into amines 2, are prepared according toMethod 45 by treatment of an appropriately substituted acetophenone withammonium formate, formic acid and formamide at temperatures ranging fromroom temperature to the reflux temperature of the solvent.

Alternatively, amines 2 wherein X equals —(CH(CH₃))— can be prepared byreduction of an appropriately substituted O-methyl oxime in the presenceof sodium borohydride and zirconium tetrachloride in a suitable solventsuch as tetrahydrofuran or diethyl ether at room temperature Method 48essentially according to the procedure of Itsuno, S., Sakurai, Y., Ito,K. Synthesis 1988, 995. The requisite O-methyl oximes can be preparedfrom the corresponding acetophenone by reaction with methoxylaminehydrochloride and pyridine in a suitable solvent such as ethanol ormethanol at temperatures ranging from room temperature to the refluxtemperature of the solvent. (Method 47)

Amines 2 for which X equals —CH(J)— where J is defined as above, can beprepared by reduction of the appropriately substituted ketone by themethods described above (Methods 45, 47, and 48). These requisiteketones, when not commercially available, can be prepared by reaction ofa suitably substituted benzaldehyde with an appropriate organometallicreagent such as phenyllithium, isopropylmagnesium bromide orethylmagnesium bromide or the like in a suitable solvent such as diethylether or tetrahydrofuran at temperatures ranging from -78° C. to 0° C.(Method 57) The resulting alcohols can be oxidized to the correspondingketone with an appropriate oxidizing agent such as chromium trioxide inaqueous sulfuric acid and acetone or pyridinium chlorochromate orpyridium dichromate in an appropriate solvent such as dichloromethane orthe like at room temperature. (Method 58)

The intermediate anilines 5 may be prepared as previously describedMethod 3A. Thus treating phenyl carbamic acid tert-butyl ester 6,wherein G is described as above, with neat trifluoroacetic acid at roomtemperature followed by neutralization with aqueous sodium hydroxideaffords the desired anilines 5. The requisite carbamic acid esters 6,wherein R₉-R₁₂ and G are described as above, are prepared as shown inMethod 2C by reaction of substituted acid chlorides, 8, where G isdescribed as above, and 4-aminophenylcarbamic acid tert-butyl esters 7,wherein R₉-R₁₂ are described above, in the presence of triethylamine inan appropriate solvent such as dichloromethane, dimethylsulfoxide, ordimethylformamide or mixturestthereof. Carboxylic acid chlorides 8 areeither commercially available or prepared from the correspondingcarboxylic acid by reaction with oxalyl chloride in a suitable solventsuch as dichloromethane at room temperature.

Alternatively, carbamic acid esters 6, wherein R₁-R₁₂ and G aredescribed as above, are prepared as shown in Method 2E by reaction ofsubstituted carboxylic acids 8a, wherein G is described as above, and anappropriately substituted 4-aminophenyl carbamic acid tert-butyl esters7 in the presence of a suitable coupling agent such asbenzotriazole-1-yloxy-tris-(dimethylamino)phosphoniumhexafluorophosphate,2-(1H-benzotriazole-1-yloxy)-1,1,3,3-tetramethyluroniumhexafluorophosphage, dicyclo-hexyl carbodiimide or the like and in thepresence of a tertiary amine base such as triethylamine ordiisopropylethylamine in a suitable solvent such as dichloromethane,dimethylformamide and the like, at room temperature to produce thecorresponding arylaminoamide.

Carboxylic acids 8a are either commercially available or are preparedaccording to literature methods. For example, when G is a substitutedthiadiazole, the acid is available from the corresponding carboxylicacid ester by reaction with an appropriate base such as sodium orpotassium hydroxide in a suitable solvent mixture such as methanol orethanol and water at room temperature.

Similarly, when G is either substituted or unsubstituted thiazole,substituted or unsubstituted oxazole, substituted or unsubstitutedisothiazole or substituted or unsubstituted isoxazole, when notcommercially available, the corresponding carboxylic acid 8a isavailable from the corresponding ethyl or methyl ester by reaction withan appropriate base such as sodium or potassium hydroxide in a suitablesolvent mixture such as methanol or ethanol and water at roomtemperature. These esters are either commercially available or can beprepared according to literature methods.

When the carboxylic acid ester precursors which are ultimately convertedto acids 8a are not commmercially available, they may be prepared bymethods known in the literature. For example,5-substituted-1,2,3-thiadiazole-4 carboxylic acid esters may be preparedessentially according to the procedure of Caron, M J. Org. Chem. 51,4075 (1986) and Taber, D. F., Ruckle, R. E. J. Amer. Chem. Soc. 108,7686 (1986). Thus, according to Method 21, treatment of a beta-ketocarboxylic acid ester with 4-methylbenzenesulfonyl azide ormethanesulfonyl azide or the like in the presence of a tertiary aminebase such triethylamine or diisopropylethylamine in a suitable solventsuch as acetonitrile affords the corresponding diazo-beta-ketocarboxylic acid ester. Treatment of this compound with2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide in asuitable solvent such as benzene or toluene or the like at temperaturesranging from room temperature to the reflux temperature of the solventgives the desired 5-substituted-1,2,3-thiadiazole-4-carboxylic acidester.

Alternatively, 4-substituted-1,2,3-thiadiazole -5-carboxylic acid estersmay be prepared essentially according to the procedure of Shafiee, A.,Lalezari, I., Yazdani, S., Shahbazian, F. M., Partovi, T. J.Pharmaceutical Sci. 65, 304 (1976). Thus, according to Method 22 and 23,reaction of an appropriately substituted beta-keto carboxylic acid esterin a suitable alcoholic solvent such as methanol or ethanol with anaqueous solution semicarbazide hydrochloride at temperatures rangingfrom room temperature to the reflux temperature of the solvent in thepresence of a suitable base such as pyridine gives correspondingsemicarbazone derivative. Treatment of this compound with neat thionylchloride at 0° C. followed by treatment with an excess aqueous solutionof sodium bicarbonate affords the corresponding4-substituted-1,2,3-thiadiazole -5-carboxylic acid esters.

4-carboalkoxythiazoles are prepared essentially according to theprocedure of Schöllkopf, U., Porsch, P., Lau, H. Liebigs Ann. Chem. 1444(1979). Thus, according to Method 55 and 56, reaction of ethylisocyanoacetate with N,N-dimethylformamide dimethyl acetal in a suitablealcoholic solvent such as ethanol at room temperature gives thecorresponding 3-dimethylamino-2-isocyano-acrylic acid ethyl ester. Asolution of this compound in a suitable solvent such as tetrahydrofuranis treated with gaseous hydrogen sulfide in the presence of a suitabletertiary amine base such as triethylamine or diiso-propylethylamine orthe like at room temperature to give the corresponding4-carboethoxy-thiazole.

Additional appropriately substituted thiazoles may be preparedessentially according to the procedure of Bredenkamp, M. W., Holzafel,C. W., van Zyl, W. J. Synthetic Comm. 20, 2235 (1990). Appropriateunsaturated oxazoles are prepared essentially according to the procedureof Henneke, K. H., Schöllkopf, U., Neudecker, T. Liebigs Ann. Chem. 1979(1979). Substituted oxazoles may be prepared essentially according tothe procedures of Galeotti, N., Montagne, C., Poncet, J., Jouin, P.Tetrahedron Lett. 33, 2807, (1992) and Shin, C., Okumura, K., Ito, A.,Nakamura, Y. Chemistry Lett. 1305, (1994).

The following specific examples are illustrative, but are not meant tobe limiting of the present invention.

EXAMPLE 1 (Method 1A) 4-Methoxy-3-trifluoromethyl-phenylamine

A suspension of 4-methoxy-3-trifluoromethyl-nitrobenzene (2.2 g) andiron powder (1.68 g) in ethanol (35 mL) and water (15 mL) is treatedwith a solution of concentrated hydrochloric acid (0.42 mL) in ethanol(6 mL) and water (3 mL) and the mixture is heated to reflux forapproximately 1 hour. The mixture is then cooled, filtered, andconcentrated under reduced pressure. The resulting oil is dissolved inethyl acetate and extracted three times with 5% aqueous hydrochloricacid. The pooled acidic extracts are then cooled in an ice bath andbasified with solid potassium carbonate, then extracted with ethylacetate. These organic extracts are washed with saturated aqueous sodiumchloride, dried over anhydrous sodium sulfate, concentrated underreduced pressure, then passed through a short column of silica gel(ethyl acetate is used as the eluant) to provide the desired compound asan amber oil.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

2,6-Dichloro-benzene-1,4-diamine

3-Chloro-4-methylsulfanyl-phenylamine

2,6-Dibromo-benzene-1,4-diamine

3-Chloro-4-trifluoromethyl-phenylamine

3-Chloro-4-ethylsulfanyl-phenylamine

4-Methoxy-3-trifluoromethyl-phenylamine

3,5-Dichloro-4-methoxy-2-methyl-phenylamine

5-Chloro-2-ethoxy-4-methoxy-phenylamine

5-Chloro-4-ethoxy-2-methoxy-phenylamine

5-Iodo-2,4-dimethoxy-phenylamine

3,5-Diiodo-2,4-dimethoxy-phenylamine

3,5-Dibromo-2,4-dimethoxy-phenylamine

5-Chloro-2-methoxy-4-methyl-phenylamine

2-Chloro-N(1),N(1)-dimethyl-benzene-1,4-diamine

3-Chloro-4-piperidin-1-yl-phenylamine

3-Chloro-4-pyrrolidin-1-yl-phenylamine

N(1)-Benzyl-2-chloro-benzene-1,4-diamine

3-Chloro-4-(4-methyl-piperazin-1-yl)-phenylamine

2-Chloro-N(1)-methyl-N(1)-(1-methyl-piperidin-4-yl)-benzene-1,4-diamine

2-Chloro-N(1)-methyl-N(1)-(1-methyl-pyrrolidin-3-yl)-benzene-1,4-diamine

2-Chloro-N(1)-methyl-N(1)-phenyl-benzene-1,4-diamine

N(1)-(1-Benzyl-pyrrolidin-3-yl)-2-chloro-N(1)-methyl-benzene-1,4-diamine

2-Chloro-N(1)-cyclopentyl-N(1)-methyl-benzene-1,4-diamine

2-[(4-Amino-2-chloro-phenyl)-(2-hydroxy-ethyl)-amino]-ethanol

2-Chloro-N(1)-hexyl-N(1)-methyl-benzene-1,4-diamine

2-Chloro-N(1)-isobutyl-N(1)-methyl-benzene-1,4-diamine

2-[(4-Amino-2-chloro-phenyl)-methyl-amino]-ethanol

2-Chloro-N(1)-(3-dimethylamino-propyl)-N(1)-methyl-benzene-1,4-diamine

2-Chloro-N(1)-(2-dimethylamino-ethyl)-N(1)-methyl-benzene-1,4-diamine

2-Chloro-N(1)-(2-dimethylamino-ethyl)-benzene-1,4-diamine

N(1)-(1-Benzyl-piperidin-4-yl)-2-chloro-benzene-1,4-diamine

2-Chloro-N(1)-(2-methoxy-ethyl)-N(1)-methyl-benzene-1,4-diamine

2-Chloro-N(1)-(3-dimethylamino-propyl)-benzene-1,4-diamine

N(1)-(1-Benzyl-pyrrolidin-3-yl)-2-chloro-benzene-1,4-diamine

3-Chloro-4-(1-methyl-piperidin-4-yloxy)-phenylamine

3-Chloro-4-(2-dimethylamino-ethoxy)-phenylamine

3-Chloro-4-(3-dimethylamino-propoxy)-phenylamine

3-Chloro-4-(1-methyl-pyrrolidin-3-yloxy)-phenylamine

3-Chloro-4-cyclohexyloxy-phenylamine

EXAMPLE 2 (Method 1B) 4-Bromo-2,4-dimethoxy-phenylamine

A suspension of 4-bromo-2,4-dimethoxy-nitrobenzene (0.48 g) and ironpowder (0.42 g) in acetic acid (10 mL) and ethanol (10 mL) is heated to120° C. for approximately 5 hours. The mixture is then cooled, filtered,and concentrated under reduced pressure. Water is added and the mixtureis cooled in an ice bath and neutralized with solid potassium carbonateand then extracted with dichloromethane. These organic extracts arewashed with saturated aqueous sodium chloride, dried over anhydroussodium sulfate, concentrated under reduced pressure, thenchromatographed over silica gel (20% ethyl acetate in hexanes is used asthe eluant) to provide the desired compound as an amber oil.

EXAMPLE 3 (Method 1C) (4-Amino-2,6-dichloro-phenoxy)-acetic AcidTert-butyl Ester

A soution of (4-nitro-2,6-dichloro-phenoxy)-acetic acid tert-butyl ester(1 g) in ethanol (17 mL) and water (8.6 mL) is treated with iron powder(0.861 g) and ammonium chloride (86 mg) and the mixture is heated toreflux for approximately 1 hour. The mixture is then filtered andconcentrated under reduced pressure. The resulting oil is partitionedbetween water and ethyl acetate, and the organic phase is then washedwith saturated aqueous sodium chloride, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure to provide the desiredcompound as a pale yellow solid.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

4-Chloro-benzene-1,2-diamine

N-(4-Amino-2-chloro-phenyl)-acetamide

(4-Amino-2,6-dichloro-phenoxy)-acetonitrile

(4-Amino-2,6-dichloro-phenoxy)-acetic acid tert-butyl ester

(2-Amino-4-chloro-5-methoxy-phenoxy)-acetonitrile

(4-Amino-2-chloro-5-methoxy-phenoxy)-acetic acid methyl ester

(4-Amino-2-chloro-5-methoxy-phenoxy)-acetic acid tert-butyl ester

(2-Amino-4-chloro-5-methoxy-phenoxy)-acetic acid tert-butyl ester

N(1)-Benzyl-4-chloro-5-methoxy-benzene-1,2-diamine

N-(4-Amino-2-chloro-phenyl)-2-fluoro-benzamide

N-(4-Amino-5-chloro-2-hydroxy-phenyl)-acetamide

N-(4-Amino-5-chloro-2-hydroxy-phenyl)-2-fluoro-benzamide

Furan-2-carboxylic acid (4-amino-2-chloro-phenyl)-amide

(4-Amino-2-chloro-phenyl)-carbamic acid ethyl ester

N-(4-Amino-5-chloro-2-methyl-phenyl)-acetamide

N-(4-Amino-5-chloro-2-methyl-phenyl)-2-fluoro-benzamide

Furan-2-carboxylic acid (4-amino-5-chloro-2-methyl-phenyl)amide

N-(4-Amino-3-chloro-phenyl)-2-fluoro-benzamide

Furan-2-carboxylic acid (4-amino-3-chloro-phenyl)-amide

N-(4-Amino-2-chloro-phenyl)-2-dimethylamino-acetamide

N-(4-Amino-2-chloro-phenyl)-2-piperidin-1-yl-acetamide

N-(4-Amino-2-chloro-phenyl)-2-morpholin-4-yl-acetamide

N-(4-Amino-2-chloro-phenyl)-methanesulfonamide

N-(4-Amino-2-chloro-phenyl)-benzamide

N-(4-Amino-2-chloro-phenyl)-2-diethylamino-acetamide

N-(4-Amino-2-chloro-phenyl)-2-pyrrolidin-1-yl-acetamide

N-(4-Amino-2-chloro-phenyl)-2-azepan-1-yl-acetamide

N-(4-Amino-2-chloro-phenyl)-2-(2-methyl-piperidin-1-yl)-acetamide

N-(4-Amino-2-chloro-phenyl)-2-(3-methyl-piperidin- 1-yl)-acetamide

3-Chloro-benzene-1,2-diamine

4-Chloro-N,N-dimethyl-benzene-1,2-diamine

EXAMPLE 4 (Method 1D) 3,5-Dichloro-4-phenoxy-phenylamine

To a slurry of 3,5-dichloro-4-phenoxy-nitrobenzene (6.1 g) and tinpowder (12 g) is added dropwise concentrated hydrochloric acid (60 mL).Ethanol (60 mL) is added and the mixture is heated to reflux forapproximately 1 hour. The mixture is then cooled in an ice bath andbasified by addition of solid sodium hydroxide. The resulting suspensionis filtered through a pad of diatomaceous earth and extracted threetimes with ethyl acetate. The combined organic extracts are then washedwith saturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure to provide the desiredproduct as a yellow solid. Recrystallization from ethyl acetate-hexanesprovided the product as a pale yellow solid.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

1-Furan-2-yl-ethylamine

3-Chloro-4-isopropoxy-phenylamine

2-Butoxy-5-chloro-4-methoxy-phenylamine

3,5-Dichloro-2-methoxy-4-methyl-phenylamine

2-Benzyloxy-5-chloro-4-methoxy-phenylamine

4-Benzyloxy-5-chloro-2-methoxy-phenylamine

5-Fluoro-2,4-dimethoxy-phenylamine

(4-Amino-2,6-dichloro-phenoxy)-acetic acid ethyl ester

3,5-Dichloro-4-phenoxy-phenylamine

2-(4-Amino-2-chloro-5-methoxy-phenoxy)-acetamide

(4-Amino-2-chloro-5-methoxy-phenoxy)-acetonitrile

2-(2-Amino-4-chloro-5-methoxy-phenoxy)-ethanol

2-(4-Amino-2-chloro-5-methoxy-phenoxy)-ethanol

4-(4-Amino-2-chloro-5-methoxy-phenoxy)-butyronitrile

4-Amino-2-chloro-5-methoxy-phenol

2-Amino-4-chloro-5-methoxy-phenol

5-Chloro-4-methoxy-2-morpholin-4-yl-phenylamine

4-Chloro-5-methoxy-N(1),N(1)-dimethyl-benzene-1,2-diamine

5-Chloro-4-methoxy-2-piperidin-1-yl-phenylamine

5-Chloro-4-methoxy-2-pyrrolidin-1-yl-phenylamine

2-Chloro-N(1)-cyclohexyl-N(1)-methyl-benzene-1,4-diamine

N(2)-Benzyl-4-methoxy-benzene-1,2-diamine

2-(4-Amino-2-chloro-phenoxy)-ethanol

2-Chloro-N(1)-cyclohexyl-N(1)-ethyl-benzene-1,4-diamine

4-Butoxy-3-chloro-phenylamine

(4-Amino-2-chloro-phenoxy)-acetonitrile

2-Chloro-N(1)-cyclohexyl-benzene-1,4-diamine

2-Chloro-N(1),N(1)-dipropyl-benzene-1,4-diamine

3-Chloro-4-(2,2,2-trifluoro-ethoxy)-phenylamine

3-Chloro-4-(octahydro-quinolin-1-yl)-phenylamine

N(1)-Allyl-2-chloro-N(1)-cyclohexyl-benzene-1,4-diamine

N-(4-Amino-2-methoxy-5-methyl-phenyl)-2-fluoro-benzamide

Furan-2-carboxylic acid (4-amino-2-methoxy-5-methyl-phenyl)amide

N-(4-Amino-naphthalen-1-yl)-2-fluoro-benzamide

3-Chloro-N,N-dimethyl-benzene-1,2-diamine

3-Chloro-4-propoxy-phenylamine

3-Iodo-4-methoxy-phenyl amine

3-Chloro-2,4-dimethoxy-aniline

3-Bromo-4-methoxy-phenylamine

3-Chloro-4-ethoxy-phenylamine

EXAMPLE 5 (Method 1E) (4-Amino-phenyl)-carbamic Acid Isobutyl Ester

To a solution of N-(4-Nitro-phenyl)-isobutyrlamide (2.0 g) in 100 mLethylene glycol monomethyl ether (100 mL) is added 10% palladium oncarbon (275 mg). The mixture is hydrogenated for 2 hours at roomtemperature under 30 psi of hydrogen on a Parr hydrogenation apparatus.The catalyst is then removed by filtration through diatomaceous earthand the filtrate is evaporated to dryness under reduced pressure byazeotroping three times with heptane. Trituration of the residue withheptane provides the desired product as a white solid.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

2-Methyl-3H-benzoimidazol-5-ylamine

N-(4-Amino-phenyl)-formamide

1H-Benzoimidazol-5-ylamine

(4-Amino-phenyl)-carbamic acid isobutyl ester

N-(4-Amino-phenyl)-isobutyramide

N-(5-Amino-pyridin-2-yl)-2-methyl-benzamide

Furan-2-carboxylic acid (5-amino-pyridin-2-yl)-amide

N-(5-Amino-pyridin-2-yl)-2-fluoro-benzamide

[6-(2,2,2-Trifluoro-acetylamino)-pyridin-3-yl]-carbamic acid tert-butylester

N-(5-Amino-pyridin-2-yl)-2,2,2-trifluoro-acetamide

(4-Amino-benzyl)-carbamic acid tert-butyl ester

2-(3,5-Bis-trifluoro methyl-phenyl)-ethyl amine

1-tert-Butyl-1H-imidazol-2-ylamine

3-(3-Dimethylamino-propyl)-5-trifluoromethyl-phenylamine

EXAMPLE 6 (Method 1F) N-(4-Amino-2-methylphenyl)-2-fluorobenzamide

A mixture of 2-fluoro-N-(2-methyl-4-nitrophenyl)benzamide (4.55 g),cyclohexene (30 mL), ethanol (70 mL), water (30 mL) and 10% palladium oncharcoal (3 g) is heated at reflux for 30 minutes. The mixture isfiltered through diatomaceous earth and concentrated under reducedpressure. The resulting oil is dissolved in 50 mL of ethyl acetate andcooled at 4° C. for 12 hours. Filtration provides the product as a tansolid.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

N-(4-Amino-2-methyl-phenyl)-acetamide

2-Methyl-benzooxazol-6-ylamine

N-(4-Amino-3-methoxy-phenyl)-acetamide

2-Acetylamino-5-amino-benzoic acid

N-(4-Amino-phenyl)-acetamide

[4-(3-Amino-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[4-(2-Amino-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

N-(4-Amino-2-cyano-phenyl)-acetamide

N-(4-Amino-2,5-dimethoxy-phenyl)-2-fluoro-benzamide

Furan-2-carboxylic acid (4-amino-2,5-dimethoxy-phenyl)-amide

N-(4-Amino-2-cyano-phenyl)-2-fluoro-benzamide

Furan-2-carboxylic acid (4-amino-2-methoxy-phenyl)-amide

N-(4-Amino-2-methoxy-phenyl)-2-fluoro-benzamide

N-(4-Amino-2-methoxy-5-methyl-phenyl)-acetamide

N-(4-Amino-2-benzoyl-phenyl)-acetamide

N-(4-Amino-2-benzoyl-phenyl)-2-fluoro-benzamide

Furan-2-carboxylic acid (4-amino-2-benzoyl-phenyl)-amide

N-(4-Amino-3-methyl-phenyl)-acetamide

N-(4-Amino-3-methyl-phenyl)-2-fluoro-benzamide

Furan-2-carboxylic acid (4-amino-3-methyl-phenyl)-amide

5-Amino-2-[(2-fluorobenzoyl)amino]-N-phenylbenzamide

Furan-2-carboxylic acid (4-amino-2-phenylcarbamoyl- phenyl)amide

N-(4-Amino-naphthalen-1-yl)-acetamide

Furan-2-carboxylic acid (4-amino-naphthalen-1-yl)-amide

N-(4-Amino-2-trifluoromethyl-phenyl)-acetamide

Furan-2-carboxylic acid (4-amino-2-cyano-phenyl)-amide

Furan-2-carboxylic acid (4-amino-2-trifluoromethyl-phenyl)-amide

N-(4-Amino-2-methyl-phenyl)-2-fluoro-benzamide

Furan-2-carboxylic acid (4-amino-2-methyl-phenyl)-amide

5-Amino-2-(2-fluoro-benzoylamino)-benzoic acid

5-Amino-2-[(furan-2-carbonyl)-amino]-benzoic acid

N-(4-Amino-2-cyano-phenyl)-2,2,2-trifluoro-acetamide

N-(4-Amino-3-methyl-phenyl)-2,6-difluoro-benzamide

N-(4-Amino-3-trifluoromethyl-phenyl)-acetamide

N-(4-Amino-3-trifluoromethyl-phenyl)-2-fluoro-benzamide

N-(4-Amino-2-trifluoromethyl-phenyl)-2,2,2-trifluoro-acetamide

N-(4-Amino-2-methoxy-phenyl)-2,2,2-trifluoro-acetamide

N-(4-Amino-2-trifluoromethyl-phenyl)-2-fluoro-N-(2-fluoro-benzoyl)-benzamide

N-(4-Amino-2-trifluoromethyl-phenyl)-2-fluoro-benzamide

EXAMPLE 7 (Method 1G)N-(4-Amino-2-chlorophenyl)-2-thiomorpholino-4-yl-acetamide

A solution of N-(2-chloro-4-nitrophenyl)-2-thiomorpholino-4-yl-acetamide(3.02 g) in ethanol (200 mL) is added to a solution of sodiumthiosulfate (12 g) in water (60 mL). The mixture is heated at reflux for12 hours, cooled and poured into water. The mixture is then extractedwith ethyl acetate. The ethyl acetate solution is washed twice withsaturated aqueous sodium chloride, dried over anhydrous potassiumcarbonate, filtered through a pad of diatomaceous earth and concentratedunder reduced pressure to give an oil. Toluene is added and the solutionchilled to give the desired product as a light orange crystalline solid.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

N-(4-Amino-2-chloro-phenyl)-2-thiomorpholin-4-yl-acetamide

N-(4-Amino-2-chloro-phenyl)-2-dipropylamino-acetamide

EXAMPLE 8 (Method 2A) (3-Chloro-4-iodo-phenyl)-carbamic Acid Tert-butylEster

To a solution of 3-chloro-4-iodo-aniline (10 g) in tetrahydrofuran (40mL) containing diiso-propylethylamine (6.9 mL) is addeddi-tert-butyl-dicarbonate (8.6 g) and the mixture is heated to reflux.After approximately 15 hours additional portions ofdiisopropylethylamine (6.9 mL) and di-tert-butyl-dicarbonate (21 g) isadded and heating is continued for approximately 24 hours. The solutionis then cooled, concentrated under reduced pressure, diluted with ethylacetate, and washed successively three times with 5% aqueoushydrochloric acid then once with saturated aqueous sodium chloride. Thesolution is dried over anhydrous sodium sulfate then concentrated underreduced pressure to provide the desired crude product as a brown oil.Crystallization is induced by addition of hexanes, and the collectedsolid material is recrystallized from hexanes to give the desiredproduct as a white solid.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

N′-(4-Nitro-benzoyl)-hydrazinecarboxylic acid tert-butyl ester

(3-Chloro-4-iodo-phenyl)-carbamic acid tert-butyl ester

(4-Bromo-3-chloro-phenyl)-carbamic acid tert-butyl ester

(3-Chloro-4-vinyl-phenyl)-carbamic acid tert-butyl ester

(3-Chloro-4-methylsulfanyl-phenyl)-carbamic acid tert-butyl ester

(4-Amino-3-chloro-phenyl)-carbamic acid tert-butyl ester

(4-Chloro-2-nitro-phenyl)-carbamic acid tert-butyl ester

(3-tert-Butoxycarbonylamino-5-chloro-phenyl)-carbamic acid tert-butylester

(4-Nitro-benzyl)-carbamic acid tert-butyl ester

(3-Bromo-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester

(2-Amino-3-chloro-5-trifluoromethyl-phenyl)-carbamic acid tert-butylester

EXAMPLE 9 (Method 2B) (3-Chloro-4-vinyl-phenyl)-carbamicAcid2-trimethylsilanyl-ethyl Ester

To a solution of 3-chloro-4-vinyl-phenylamine (3.4 g) inN,N-dimethylformamide (44 mL) containing diisopropylethylamine (5.8 mL)is added 1-[2-(trimethylsilyl)- ethoxycarbonyl-oxy]benzotriazole (7.1 g)and the mixture is stirred at room temperature under an atmosphere ofargon for three days. The solution is then diluted with water andextracted three times with diethyl ether. The combined organic extractsare washed successively with water, saturated aqueous sodium chloride,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The resulting residue is chromatographed over silica gel (10%ethyl acetate in hexanes is used as the eluant) to provide the desiredproduct as a yellow oil.

EXAMPLE 10 (Method 2C) [4-(2-Fluoro-benzoylamino)-phenyl]-carbamic Acidtert-butyl Ester

To a solution of mono-N-(t-butoxycarbonyl)-1,4-phenylenediamine (1.58 g)and triethylamine (1.50 mL) in 25 mL of dichloromethane is addedo-fluorobenzoyl chloride (1.20 g). A solid formed immediately forms andis filtered and washed with fresh solvent to yield a white solid, 1.90g.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

N-(3-Methoxy-4-nitro-phenyl)-acetamide

N-(4-Amino-phenyl)-isobutyrlamide

2,2,2-Trifluoro-N-(2-methoxy-4-nitro-phenyl)-acetamide

[4-(2-Methyl-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

Acetic acid 2-(4-tert-butoxycarbonylamino-phenylcarbamoyl)-phenyl ester

[4-(4-Fluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[4-(3-Fluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[4-(2-Fluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[4-(2-Methoxy-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[4-(3-Methoxy-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[4-(4-Methoxy-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[4-(2,2-Dimethyl-propionylamino)-phenyl]-carbamic acid tert-butyl ester

[4-(2-Bromo-acetylamino)-phenyl]-carbamic acid tert-butyl ester

[4-(2,2,2-Trifluoro-acetylamino)-phenyl]-carbamic acid tert-butyl ester

(4-Benzoylamino-phenyl)-carbamic acid tert-butyl ester

(4-Methanesulfonylamino-phenyl)-carbamic acid tert-butyl ester

(4-Phenylacetylamino-phenyl)-carbamic acid tert-butyl ester

{4-[(Thiophene-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester

[4-(3-Nitro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[4-(3-Acetylamino-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[4-(3-Methanesulfonylamino-benzoylamino)-phenyl]-carbamic acidtert-butyl ester

Ethyl[3-[[[4-[[(1,1-dimethylethoxy)carbonyl]amino]phenyl]amino]carbonyl]phenyl]carbamate

[4-(2-Trifluoromethyl-benzoylamino)-phenyl]-carbamic acid tert-butylester

[4-(2,6-Difluoro -benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[4-(2-Chloro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[4-(2-Bromo-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[4-(2-Nitro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

{(4-[(Benzo [b]thiophene-2-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester

{(4-[(Pyridine-4-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester

{(4-[(Naphthalene-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butylester

{4-[(Naphthalene-1-carbonyl)-amino]-phenyl)}-carbamic acid tert-butylester

{(4-[(3-Bromo-thiophene-2-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester

{4-[(Biphenyl-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester

N-(4-tert-Butoxycarbonylamino-phenyl)-phthalamic acid

[4-(2,3-Difluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[4-(2,5-Difluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[4-(2,4-Difluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[4-(2-Acetylamino-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[4-(2-Methanesulfonylamino-benzoylamino)-phenyl]-carbamic acidtert-butyl ester

[4-(2,3,4-Trifluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[4-(2,3,4,5,6-Pentafluoro-benzoylamino)-phenyl]-carbamic acid tert-butylester

N-(4-tert-Butoxycarbonylamino-phenyl)-isophthalamic acid methyl ester

2-Methylsulfanyl-N-[4-(2,2,2-trifluoro-acetylamino)-phenyl]-benzamide

[4-(3-Benzyloxy-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[4-(3-Butoxy-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

{4-[(5-Difluoromethyl-furan-2-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester

{4-[(Thiophene-3-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester

{4-[(5-Methyl-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butylester

{4-[(5-Bromo-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butylester

(4-Hexanoylamino-phenyl)-carbamic acid tert-butyl ester

[4-(2-Thiophen-2-yl-acetylamino)-phenyl]-carbamic acid tert-butyl ester

{4-[(Pyridine-3-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester

{4-[(4-Bromo-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butylester

{4-[(Furan-3-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester

(4-Phenoxycarbonylamino-phenyl)-carbamic acid tert-butyl ester

{4-[(Benzo[1,3]dioxole-4-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester

[4-(3-Trifluoromethoxy-benzoylamino)-phenyl]-carbamic acid tert-butylester

N-(2,5-Dimethoxy-4-nitro-phenyl)-2-fluoro-benzamide

{4-[(Furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester

[4-(2-Phenoxy-acetylamino)-phenyl]-carbamic acid tert-butyl ester

{4-[(5-Nitro-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butylester

{4-[(5-Chloro-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butylester

{4-[(3-Methyl-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butylester

[4-(2-Methoxy-acetylamino)-phenyl]-carbamic acid tert-butyl ester

{4-[(4-Furan-3-yl-[1,2,3]thiadiazole-5-carbonyl)-amino]-phenyl}-carbamicacid tert-butyl ester

{4-[(5-tert-Butyl-furan-2-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester

N-[3-Cyano-4-(2,2,2-trifluoro-acetylamino)-phenyl]-2-fluoro-benzamide

Furan-2-carboxylic acid[3-cyano-4-(2,2,2-trifluoro-acetylamino)-phenyl]amide

N-(4-Acetylamino-2-cyano-phenyl)-2,2,2-trifluoro-acetamide

2,2,2-Trifluoro-N-(4-nitro-2-trifluoromethyl-phenyl)-acetamide

N-(4-Acetylamino-2-trifluoromethyl-phenyl)-2,2,2-trifluoro-acetamide

2-Fluoro-N-[4-(2,2,2-trifluoro-acetylamino)-3-trifluoromethyl-phenyl]benzamide

Furan-2-carboxylic acid[4-(2,2,2-trifluoro-acetylamino)-3-trifluoromethyl-phenyl]amide

2-Fluoro-N-(2-methyl-benzooxazol-6-yl)-benzamide

4-(2-Fluoro-benzoylamino)-2-hydroxy-benzoic acid phenyl ester

{4-[(Isoxazole-5-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester

N-(4-Acetylamino-2-methoxy-phenyl)-2,2,2-trifluoro-acetamide

2-Fluoro-N-[3-methoxy-4-(2,2,2-trifluoro-acetylamino)-phenyl]benzamide

2-Fluoro-N-(2-fluoro-benzoyl)-N-(4-nitro-2-trifluoromethyl-phenyl)benzamide

{4-[(1H-Pyrazole-4-carbonyl)-amino]-phenyl}-carbamic acid tert-butylester

{4-[(4H-Imidazole-4-carbonyl)-amino]-phenyl}-carbamic acid tert-butylester

{4-[(5-Methyl-[1,2,3]thiadiazole-4-carbonyl)-amino]-phenyl}-carbamicacid tert-butyl ester

{4-[(5-Furan-3-yl-[1,2,3]thiadiazole-4-carbonyl)-amino]-phenyl}-carbamicacid tert-butyl ester

2,2,2-Trifluoro-N-(5-nitro-pyridin-2-yl)-acetamide

{4-[(1-Methyl-1H-pyrazole-4-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester

4-(2-Fluoro-benzoylamino)-2-hydroxy-benzoic acid methyl ester

N-(5-Chloro-2,4-dimethoxy-phenyl)-oxalamic acid

Isoxazole-5-carboxylic acid (4-amino-phenyl)-amide

2-Fluoro-N-(4-nitro-benzyl)-benzamide

Furan-2-carboxylic acid 4-nitro-benzylamide

N-[3-Chloro-5-(2,2,2-trifluoro-acetylamino)-phenyl]-2,2,2-trifluoro-acetamide

N-(3-Amino-5-chloro-phenyl)-2,2,2-trifluoro-acetamide

[4-(2-Fluoro-benzoylamino)-benzyl]-carbamic acid tert-butyl ester

[4-(2,6-Difluoro-benzoylamino)-benzyl]-carbamic acid tert-butyl ester

2,6-Difluoro-N-(4-nitro-benzyl)-benzamide

{4-[(Furan-2-carbonyl)-amino]-benzyl}-carbamic acid tert-butyl ester

N-(3-Amino-5-chloro-phenyl)-acetamide

[4-(3-Chloro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[4-(4-Chloro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[4-(4-Dimethylamino-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

(4-Benzenesulfonylamino-phenyl)-carbamic acid tert-butyl ester

[4-(3-Trifluoromethyl-benzoylamino)-phenyl]-carbamic acid tert-butylester

2,2,2-Trifluoro-N-(5-nitro-pyrimidin-2-yl)-acetamide

EXAMPLE 11 (Method 2D) 2-Chloro-N-(2-chloro-4-nitrophenyl)acetamide

A solution of 2-chloro-4-nitroaniline (19.0 g) and chloroacetyl chloride(30 mL) in tetrahydrofuran (150 mL) is heated at reflux for 1 hour. Thesolution is cooled and concentrated under reduced pressure, giving a wetyellow solid. Ether (250 mL) is added and the yellow solid is collected.

Using the above procedure and appropriate starting materias thefollowing compounds were prepared:

N-(4-Nitro-3-trifluoromethyl-phenyl)-acetamide

(2-Chloro-4-nitro-phenyl)-carbamic acid ethyl ester

2-Acetylamino-5-nitro-benzoic acid

Furan-2-carboxylic acid (5-chloro-2-hydroxy-4-nitro-phenyl)-amide

Furan-2-carboxylic acid (2-methyl-4-nitro-phenyl)-amide

Furan-2-carboxylic acid (2-methoxy-4-nitro-phenyl)-amide

N-(2-Chloro-4-nitro-phenyl)-benzamide

2-Methoxy-N-(4-nitro-phenyl)-acetamide

N-(4-Nitro-phenyl)-acrylamide

N-(4-Nitro-phenyl)-isobutyrlamide

[4-)acryloylamino)-phenyl]carbamic acid tert-butyl ester

(4-Nitro-phenyl)-carbamic acid isobutyl ester

[1,2,3]Thiadiazole-4-carboxylic acid (5-nitro-pyridin-2-yl)-amide

Furan-2-carboxylic acid (5-nitro-pyridin-2-yl)-amide

2-Fluoro-N-(5-nitro-pyridin-2-yl)-benzamide

N-(2-Chloro-4-nitro-phenyl)-2-fluoro-benzamide

Furan-2-carboxylic acid (2,5-dimethoxy-4-nitro-phenyl)-amide

N-(2-Cyano-4-nitro-phenyl)-2-fluoro-benzamide

2-Fluoro-N-(2-methoxy-4-nitro-phenyl)-benzamide

2-Methyl-N-(5-nitro-pyridin-2-yl)-benzamide

Furan-2-carboxylic acid (2-methoxy-5-methyl-4-nitro-phenyl)-amide

2-Fluoro-N-(2-methoxy-5-methyl-4-nitro-phenyl)-benzamide

N-(2-Benzoyl-4-nitro-phenyl)-acetamide

N-(2-Benzoyl-4-nitro-phenyl)-2-fluoro-benzamide

Furan-2-carboxylic acid (2-benzoyl-4-nitro-phenyl)-amide

N-(3-Methyl-4-nitro-phenyl)-acetamide

2-Fluoro-N-(3-methyl-4-nitro-phenyl)-benzamide

Furan-2-carboxylic acid (3-methyl-4-nitro-phenyl)-amide

2-Acetylamino-5-nitro-N-phenyl-benzamide

2-[(2-Fluorobenzoyl)amino]-5-nitro-N-phenylbenzamide

Furan-2-carboxylic acid (4-nitro-2-phenylcarbamoyl-phenyl)-amide

2-Fluoro-N-(4-nitro-naphthalen-1-yl)-benzamide

Furan-2-carboxylic acid (4-nitro-naphthalen-1-yl)-amide

N-(5-Chloro-2-hydroxy-4-nitro-phenyl)-acetamide

N-(5-Chloro-2-hydroxy-4-nitro-phenyl)-2-fluoro-benzamide

Furan-2-carboxylic acid (2-chloro-4-nitro-phenyl)-amide

N-(4-Nitro-2-trifluoromethyl-phenyl)-acetamide

Furan-2-carboxylic acid (2-cyano-4-nitro-phenyl)-amide

2-Fluoro-N-(4-nitro-2-trifluoromethyl-phenyl)-benzamide

Furan-2-carboxylic acid (4-nitro-2-trifluoromethyl-phenyl)-amide

2-Fluoro-N-(2-methyl-4-nitro-phenyl)-benzamide

N-(5-Chloro-2-methyl-4-nitro-phenyl)-2-fluoro-benzamide

Furan-2-carboxylic acid (5-chloro-2-methyl-4-nitro-phenyl)-amide

2-(2-Fluoro-benzoylamino)-5-nitro-benzoic acid

2-[(Furan-2-carbonyl)-amino]-5-nitro-benzoic acid

N-(3-Chloro-4-nitro-phenyl)-2-fluoro-benzamide

Furan-2-carboxylic acid (3-chloro-4-nitro-phenyl)-amide

2,6-Difluoro-N-(3-methyl-4-nitro-phenyl)-benzamide

2-Fluoro-N-(4-nitro-3-trifluoromethyl-phenyl)-benzamide

Furan-2-carboxylic acid (4-nitro-3-trifluoromethyl-phenyl)-amide

2-Chloro-N-(2-chloro-4-nitro-phenyl)-acetamide

N-(2-Chloro-4-nitrophenyl)methanesulfonamide

Furan-2-carboxylic acid[3-methoxy-4-(2,2,2-trifluoro-acetylamino)-phenyl]-amide

N-(2-Chloro-4-nitro-phenyl)-2,2,2-trifluoro-acetamide

EXAMPLE 12{4-[(4-Phenyl-[1,2,3]thiadiazole-5-carbonyl)-amino]-phenyl}-carbamicacid tert-butyl

A solution of 1-(N-tert-butoxycarbonyl)-1,4-phenylenediamine (0.8 g) and4-phenyl-[1,2,3]thiadiazole-5-carboxylic acid (0.7 g) in dichloromethane(10 mL) is treated with triethylamine (1.3 mL) andbenzotriazole-l-yloxy-tris(dimethylamino)- phosphoniumhexa-fluorophosphate (1.6 g). After stirring at room temperature, thereaction is diluted with water and extracted with dichloromethane. Theorganic layer is washed with 0.5 N hydrochloric acid, saturated sodiumbicarbonate, and water then dried over magnesium sulfate, filtered, andconcentrated under reduced pressure to give the desired product.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

{4-[(1H-Pyrrole-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butylester

{4-[(Pyrazine-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester

{4-[(5-Methyl-thiophene-2-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester

{4-[(1-Methyl-1H-pyrrole-2-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester

{4-[(Quinoline-8-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester

{4-[(Benzofuran-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butylester

{4-[(Isoquinoline-1-carbonyl)-amino]-phenyl}-carbamic acid tert-butylester

{4-[(Quinoline-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester

{4-[(Pyridine-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester

{4-[(Isoquinoline-4-carbonyl)-amino]-phenyl }-carbamic acid tert-butylester

{4-[([1,2,3]Thiadiazole-4-carbonyl)-amino]-phenyl)-carbamic acidtert-butyl ester

{4-[(1H-[1,2,3]Triazole-4-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester

[4-(2-Methylsufanyl-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

{4-[(Quinoline-4-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester

{4-[(4-Methyl-[1,2,3]thiadiazole-5-carbonyl)-amino]-phenyl}-carbamicacid tert-butyl ester

{4-[(4-Phenyl-[1,2,3]thiadiazole-5-carbonyl)-amino]-phenyl}-carbamicacid tert-butyl ester

{4-[(1H-Indole-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester

[1,2,3]Thiadiazole-4-carboxylic acid 4-nitro-benzylamide

{4-[([1,2,3]Thiadiazole-4-carbonyl)-amino]-benzyl}-carbamic acidtert-butyl ester

Acetic acid 4-(4-tert-butoxycarbonylamino-phenylcarbamoyl)-phenyl ester

{4-[(Quinoline-6-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester

EXAMPLE 13 (Method 2F) Acetic acid2-(4-tert-butoxycarbonylamino-2,6-dichloro-phenoxy)-ethyl Ester

A solution of [3,5-dichloro-4-(2-hydroxy-ethoxy)-phenyl]-carbamic acidtert-butyl ester (0.85 g) in pyridine (14 mL) is treated with aceticanhydride (1.24 mL) and the mixture is stirred at room temperature for15 hours. The solvent is removed under reduced pressure and the residuedissolved in ethyl acetate. This solution is then washed twice with 5%aqueous hydrochloric acid, once with saturated aqueous sodiumbicarbonate, and then with saturated aqueous sodium chloride. Thesolution is dried over anhydrous magnesium sulfate and the solvent isremoved under reduced pressure to provide the desired product as acolorless oil.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

Phenylsulfanyl-acetonitrile

Acetic acid 2-(4-tert-butoxycarbonylamino-2,6-dichloro-phenoxy)-ethylester

EXAMPLE 14 (Method 2G) (3,5-Dichloro-4-hydroxy-phenyl)-carbamic AcidTert-butyl Ester

To a solution of 2,6-dichloro-4-amino phenol (9.5 g) in tetrahydrofuran(130 mL) is added di-tert-butyl-dicarbonate (11.7 g) and the mixture isheated to reflux for approximately 15 hours. The solution is thencooled, concentrated under reduced pressure, diluted with ethyl acetate,and washed successively three times with 5% aqueous hydrochloric acidthen once with saturated aqueous sodium chloride. The solution is driedover anhydrous sodium sulfate then concentrated under reduced pressureto provide the desired crude product. This material is then trituratedwith cold dichloromethane to provide the product as a white solid.

Using the above procedure and appropriate starting materials thefollowing compound was prepared:

(3-Amino-5-chloro-phenyl)-carbamic acid tert-butyl ester

EXAMPLE 15 (Method 3A) 3,5-Dichloro-4-ethoxy-phenylamine

Trifluoroacetic acid (5 mL) is added to solid(3,5-dichloro-4-ethoxy-phenyl)-carbamic acid tert-butyl ester (0.97 g)and the mixture is stirred for approximately 45 minutes at roomtemperature. Water is then added, and the mixture is cooled in an icebath and basified with solid potassium carbonate. The solution isextracted three times with ethyl acetate and the combined organic phasesare washed with saturated aqueous sodium chloride then dried overanhydrous sodium sulfate. Concentration under reduced pressure andrecrystallization from hexanes provides the desired product as a paleyellow crystalline solid.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

5-Bromo-pyridin-3-ylamine

3-Chloro-4-methanesulfonyl-phenylamine

N-(4-Amino-phenyl)-2-methyl-benzamide

Acetic acid 2-(4-amino-phenylcarbamoyl)-phenyl ester

N-(4-Amino-phenyl)-4-fluoro-benzamide

N-(4-Amino-phenyl)-3-fluoro-benzamide

N-(4-Amino-phenyl)-2-fluoro-benzamide

N-(4-Amino-phenyl)-2-methoxy-benzamide

N-(4-Amino-phenyl)-3-methoxy-benzamide

N-(4-Amino-phenyl)-4-methoxy-benzamide

N-(4-Amino-phenyl)-2-phenyl-acetamide

N-(4-Amino-phenyl)-2,2-dimethyl-propionamide

N-(4-Amino-phenyl)-2,2,2-trifluoro-acetamide

Thiophene-2-carboxylic acid (4-amino-phenyl)-amide

1H-Pyrrole-2-carboxylic acid (4-amino-phenyl)-amide

N-(4-Amino-phenyl)-3-nitro-benzamide

3-Acetylamino-N-(4-amino-phenyl)-benzamide

N-(4-Amino-phenyl)-3-dimethylamino-benzamide

N-(4-Amino-phenyl)-3-methanesulfonylamino-benzamide

N-(4-Amino-phenyl)-2-trifluoromethyl-benzamide

N-(4-Amino-phenyl)-2,6-difluoro-benzamide

N-(4-Amino-phenyl)-2-chloro-benzamide

N-(4-Amino-phenyl)-2-bromo-benzamide

N-(4-Amino-phenyl)-2-nitro-benzamide

Pyrazine-2-carboxylic acid (4-amino-phenyl)-amide

5-Methyl-thiophene-2-carboxylic acid (4-amino-phenyl)-amide

Quinoline-8-carboxylic acid (4-amino-phenyl)-amide

1-Methyl-1H-pyrrole -2-carboxylic acid (4-amino-phenyl )-amide

Benzo[b]thiophene-2-carboxylic acid (4-amino-phenyl)-amide

Benzofuran-2-carboxylic acid (4-amino-phenyl)-amide

N-(4-Amino-phenyl)-isonicotinamide

Naphthalene-2-carboxylic acid (4-amino-phenyl)-amide

Naphthalene-1-carboxylic acid (4-amino-phenyl)-amide

Isoquinoline-1-carboxylic acid (4-amino-phenyl)-amide

Quinoline-2-carboxylic acid (4-amino-phenyl)-amide

3,5-Dichloro-4-ethoxy-phenylamine

4-Butoxy-3,5-dichloro-phenylamine

Isoquinoline-4-carboxylic acid (4-amino-phenyl)-amide

[1,2,3]Thiadiazole-4-carboxylic acid (4-amino-phenyl)-amide

1H-[1,2,3]Triazole-4-carboxylic acid (4-amino-phenyl)-amide

3-Bromo-thiophene-2-carboxylic acid (4-amino-phenyl)-amide

4-Benzyloxy-3,5-dichloro-phenylamine

2-(4-Amino-2,6-dichloro-phenoxy)-acetamide

(4-Amino-2,6-dichloro-phenoxy)-acetic acid methyl ester

[3-(4-Amino-phenylcarbamoyl)-phenyl]-carbamic acid ethyl ester

2-Amino-N-(4-amino-phenyl)-benzamide

Biphenyl-2-carboxylic acid (4-amino-phenyl)-amide

N-(4-Amino-phenyl)-2,3-difluoro-benzamide

N-(4-Amino-phenyl)-2,5-difluoro-benzamide

N-(4-Amino-phenyl)-2,4-difluoro-benzamide

2-Acetylamino-N-(4-amino-phenyl)-benzamide

N-(4-Amino-phenyl)-2-methanesulfonylamino-benzamide

N-(4-Amino-phenyl)-2,3,4-trifluoro-benzamide

N-(4-Amino-phenyl)-2,3,4,5,6-pentafluoro-benzamide

N-(4-Amino-phenyl)-2-methylsulfanyl-benzamide

Acetic acid 2-(4-amino-2,6-dichloro-phenoxy)-ethyl ester

N-(4-Amino-phenyl)-isophthalamic acid methyl ester

N-(4-Amino-phenyl)-3-benzyloxy-benzamide

N-(4-Amino-phenyl)-3-butoxy-benzamide

[3-(4-Amino-phenylcarbamoyl)-phenoxy]-acetic acid ethyl ester

Pyridine-2-carboxylic acid (4-amino-phenyl)-amide

Quinoline-4-carboxylic acid (4-amino-phenyl)-amide

5-Methyl-furan-2-carboxylic acid (4-amino-phenyl)-amide

5-Difluoromethyl-furan-2-carboxylic acid (4-amino-phenyl)-amide

1H-Indole-2-carboxylic acid (4-amino-phenyl)-amide

4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid (4-amino-phenyl)-amide

Thiophene-3-carboxylic acid (4-amino-phenyl)-amide

5-Chloro-furan-2-carboxylic acid (4-amino-phenyl)-amide

5-Nitro-furan-2-carboxylic acid (4-amino-phenyl)-amide

N-(4-Amino-phenyl)-2-thiophen-2-yl-acetamide

3-Methyl-furan-2-carboxylic acid (4-amino-phenyl)-amide

5-Bromo-furan-2-carboxylic acid (4-amino-phenyl)-amide

4-Bromo-furan-2-carboxylic acid (4-amino-phenyl)-amide

N-(4-Amino-phenyl)-nicotinamide

N-(4-Aminophenyl)-3-furancarboxamide

4-Phenyl-[1,2,3]thiadiazole-5-carboxylic acid (4-amino-phenyl)-amide

Acetic acid 3-(4-amino-phenylcarbamoyl)-phenyl ester

Benzo[1,3]dioxole-4-carboxylic acid (4-amino-phenyl)-amide

N-(4-Amino-phenyl)-3-(2-dimethylamino-ethoxy)-benzamide

N-(4-Amino-phenyl)-3-trifluoromethoxy-benzamide

N-(4-Amino-phenyl)-3-(2-morpholin-4-yl-ethoxy)-benzamide

(4-Amino-phenyl)-carbamic acid hexyl ester

Furan-2-carboxylic acid (4-amino-phenyl)-amide

(4-Amino-phenyl)-carbamic acid phenyl ester

Hexanoic acid (4-amino-phenyl)-amide

N-(4-Amino-phenyl)-acrylamide

N-(4-Amino-phenyl)-2-methoxy-acetamide

4-Furan-3-yl-[1,2,3]thiadiazole-5-carboxylic acid (4-amino-phenyl)-amide

5-tert-Butyl-furan-2-carboxylic acid (4-amino-phenyl)-amide

3-Chloro-4-methanesulfinyl-phenylamine

5-Methyl-[1,2,3]thiadiazole-4-carboxylic acid (4-amino-phenyl)-amide

2-(4-Amino-2-chloro-phenyl)-ethanol

(4-Amino-2-chloro-phenyl)-carbamic acid 2-piperidin-1-yl-ethyl ester

5-Chloro-N,N-dimethyl-benzene-1,3-diamine

3-(2-Methyl-butyl)-5-trifluoromethyl-phenylamine

3-Isobutyl-5-trifluoromethyl-phenylamine

Furan-2-carboxylic acid (4-aminomethyl-phenyl)-amide

N-(4-Aminomethyl-phenyl)-2-fluoro-benzamide

[1,2,3]Thiadiazole-4-carboxylic acid (4-aminomethyl-phenyl)-amide

N-(4-Aminomethyl-phenyl)-2,6-difluoro-benzamide

Oxazole-4-carboxylic acid (4-amino-phenyl)-amide

N-(4-Amino-phenyl)-3-chloro-benzamide

N-(4-Amino-phenyl)-4-chloro-benzamide

Acetic acid 4-(4-amino-phenylcarbamoyl)-phenyl ester

N-(4-Amino-phenyl)-4-dimethylamino-benzamide

1-(4-Amino-phenyl)-3-(3,5-bis-trifluoromethyl-phenyl)-thiourea

N-(4-Amino-phenyl)-2-iodo-benzamide

N-(4-Amino-phenyl)-3-trifluoromethyl-benzamide

EXAMPLE 16 (Method 3B) 1-(4-Amino-2-chloro-phenyl)-ethanol

A 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (5.7 mL)is added to [3-chloro-4-(1-hydroxy-ethyl)-phenyl]-carbamic acid2-trimethylsilanyl-ethyl ester (0.5 g) and the mixture is stirred atroom temperature for approximately 3.5 hours. The solution is thenconcentrated under reduced pressure, dissolved in a 1:1 mixture of ethylacetate and hexanes, washed successively with water then saturatedaqueous sodium chloride, and dried over anhydrous magnesium sulfate.Removal of the solvent under reduced pressure followed by chromatographyover silica gel (40% ethyl acetate in hexanes is used as the eluant)provides the product as an amber oil.

EXAMPLE 17 (Method 3C) N-(4-Amino-3-cyanophenyl)-2-fluoro-benzamide

Potassium carbonate (5.0 g) is added to a solution ofN-[3-cyano-4-(2,2,2-trifluoroacetyl-amino)-phenyl]-2-fluoro-benzamide(2.5 g) in methanol (270 mL) and water (16 mL) and the mixture isrefluxed overnight. After removing the solvent under reduced pressure,the residue is suspended in water and extracted with dichloromethane.The organic extracts are pooled, washed with water and then saturatedaqueous sodium chloride, dried over anhydrous magnesium sulfate,filtered and concentrated under reduced pressure to provide the desiredcompound as a white solid.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

N-(4-Amino-phenyl)-2-methanesulfinyl-benzamide

N-(4-Amino-3-cyano-phenyl)-2-fluoro-benzamide

Furan-2-carboxylic acid (4-amino-3-cyano-phenyl)-amide

N-(4-Amino-3-cyano-phenyl)-acetamide

Furan-2-carboxylic acid (4-amino-3-trifluoromethyl-phenyl)-amide

N-(4-Amino-3-methoxy-phenyl)-acetamide

N-(4-Amino-3-methoxy-phenyl)-2-fluoro-benzamide

Furan-2-carboxylic acid (4-amino-3-methoxy-phenyl)-amide

EXAMPLE 17 (Method 4A) 2-Chloro-1-cyclohexyloxy-4-nitro-benzene

Cylcohexanol (2.9 g) in dimethylsulfoxide (20 mL) is added slowly to aflask containing potassium hydride (0.90 g, pre-washed three times withhexanes) under an atmosphere of argon and the solution is stirred forabout 1 hour at room temperature. A solution of3-chloro-4-fluoro-nitrobenzene (1 g) in dimethylsulfoxide (10 mL) isadded and the resulting dark red colored solution is then heated forthree hours to approximately 100 degrees. The reaction mixture is thencooled, diluted with diethyl ether (300 mL), and washed successivelywith saturated aqueous ammonium chloride, three times with water, thenwith saturated aqueous sodium chloride. The organic layer is then driedover anhydrous magnesium sulfate, the solvent is removed under reducedpressure, and the resulting oil is chromatographed over silica gel (5%ethyl acetate in hexanes is used as the eluant) to provide the desiredproduct as an orange solid.

EXAMPLE 18 (Method 4C)(2-Chloro-4-nitro-phenyl)-methyl-(1-methyl-pyrrolidin-3-yl)-amine

3-Chloro-4-fluoronitrobenzene (1.0 g) andN,N′-dimethyl-3-aminopyrrolidine (1.72 g) are combined and stirred forapproximately 24 hours. The mixture is then diluted with ethyl acetate,washed twice with water and once with saturated sodium chloride, anddried over anhydrous sodium sulfate. After removal of the solvent underreduced pressure the residue is chromatographed over silica gel (pureethyl acetate followed by pure methanol is used as the eluants) toprovide the desired product as a yellow oil.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

(2-Chloro-4-nitro-phenyl)-dipropyl-amine

1-(2-Chloro-4-nitro-phenyl)-piperidine

1-(2-Chloro-4-nitro-phenyl)-pyrrolidine

(2-Chloro-4-nitro-phenyl)-cyclohexyl-methyl-amine

Benzyl-(2-chloro-4-nitro-phenyl)-amine

(2-Chloro-4-nitro-phenyl)-methyl-(1-methyl-piperidin-4-yl)-amine

(2-Chloro-4-nitro-phenyl)-cyclohexyl-ethyl-amine

(2-Chloro-4-nitro-phenyl)-cyclohexyl-amine

(2-Chloro-4-nitro-phenyl)-methyl-(1-methyl-pyrrolidin-3-yl)-amine

(1-Benzyl-pyrrolidin-3-yl)-(2-chloro-4-nitro-phenyl)-methyl-amine

(2-Chloro-4-nitro-phenyl)-cyclopentyl-methyl-amine

1-(2-Chloro-4-nitro-phenyl)-decahydro-quinoline

Allyl-(2-chloro-4-nitro-phenyl)-cyclohexyl-amine

2-[(2-Chloro-4-nitro-phenyl)-(2-hydroxy-ethyl)-amino]-ethanol

(2-Chloro-4-nitro-phenyl)-isobutyl-methyl-amine

(2-Chloro-4-nitro-phenyl)-hexyl-methyl-amine

2-[(2-Chloro-4-nitro-phenyl)-methyl-amino]-ethanol

N-(2-Chloro-4-nitro-phenyl)-N,N′,N′-trimethyl-ethane-1,2-diamine

N-(2-Chloro-4-nitro-phenyl)-N,N′,N′-trimethyl-propane-1,3-diamine

(1-Benzyl-piperidin-4-yl)-(2-chloro-4-nitro-phenyl)-amine

N-(2-Chloro-4-nitro-phenyl)-N′,N′-dimethyl-ethane-1,2-diamine

N-(2-Chloro-4-nitro-phenyl)-N′,N′-dimethyl-propane-1,3-diamine

(2-Chloro-4-nitro-phenyl)-(2-methoxy-ethyl)-methyl-amine

(1-Benzyl-pyrrolidin-3-yl)-(2-chloro-4-nitro-phenyl)-amine

4-Piperidin-1-yl-3-trifluoromethyl-benzonitrile

4-Dimethylamino-3-trifluoromethyl-benzonitrile

4-(4-Methyl-piperazin-1-yl)-3-trifluoromethyl-benzonitrile

EXAMPLE 19 (Method 4E) Butyl-(2-chloro-4-nitro-phenyl)thioether

A solution of 3-chloro-4-fluoro-nitrobenzene (5.0 g) and sodium sulfide(2.5 g) in N,N-dimethylformamide (30 mL) is stirred at room temperaturefor 1 hour and then treated with 1-iodobutane (12.6 g). The solvent isthen removed under reduced pressure and the resulting residue is treatedwith ethyl acetate and hexanes to precipitate the inorganic salts. Thesolids are removed by filtration and the filtrate is reduced underreduced pressure. The resulting residue is then passed through hydrousmagnesium silicate using dichloromethane as the eluent to provide thedesired compound as a yellow solid.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

1-Butylsulfanyl-2-chloro-4-nitro-benzene

2-Chloro-1-cyclohexylsulfanyl-4-nitro-benzene

2-Chloro-1-ethylsulfanyl-4-nitro-benzene

EXAMPLE 20 (Method 4F)(4-Chloro-5-methoxy-2-nitro-phenyl)-dimethyl-amine

To a solution of trifluoro-methanesulfonic acid4-chloro-5-methoxy-2-nitro-phenyl ester (1.0 g) in tetrahydrofuran (2.0mL) is added dimethylamine (4.0 mL of a 40% aqueous solution) and themixture is stirred at room temperature for approximately 15 hours. Thesolution is then concentrated under reduced pressure and the residue isdissolved in ethyl acetate and then washed with water. The aqueous layeris extracted once with ethyl acetate and the combined organic layers arewashed with saturated aqueous sodium chloride and dried over anhydroussodium sulfate. The solvent is removed by evaporation under reducedpressure and the residue is triturated with hexanes to provide thedesired product as a colorless solid.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

(4-Chloro-2-nitro-phenyl)-dimethyl-amine

4-(4-Chloro-5-methoxy-2-nitro-phenyl)-morpholine

(4-Chloro-5-methoxy-2-nitro-phenyl)-dimethyl-amine

1-(4-Chloro-5-methoxy-2-nitro-phenyl)-piperidine

1-(4-Chloro-5-methoxy-2-nitro-phenyl)-pyrrolidine

Benzyl-(4-chloro-5-methoxy-2-nitro-phenyl)-amine

(2-Chloro-6-nitro-phenyl)-dimethyl-amine

EXAMPLE 21 (Method 4G) (2-Chloro-4-nitro-phenyl)-methyl-phenyl-amine

n-Butyl lithium (12.3 mL of a 2.5 M solution in hexanes) is addeddropwise to a solution of N-methyl aniline (3.0 g) in tetrahydrofuran(75 mL) at 0° C. The mixture is allowed to warm slowly to roomtemperature and is then re-cooled to 0° C. and added by cannula to asolution of 3-chloro-4-fluoronitrobenzene (4.9 g) in tetrahydrofuran (35mL) that is kept at −78° C. Following the addition, the reaction mixtureis permitted to warm to room temperature over the course of 1 hour, andis then concentrated under reduced pressure, quenched by addition ofsaturated aqueous ammonium chloride, and extracted three times withethyl acetate. The pooled organic layers are washed three times with 5%aqueous hydrochloric acid, once with water, once with saturated aqueoussodium bicarbonate, once with saturated aqueous sodium chloride, andthen dried over anhydrous magnesium sulfate. Following removal of thesolvent under reduced pressure the residue is chromatographed oversilica gel (5% diethyl ether in hexanes is used as the eluant) toprovide the desired product as a clear colorless oil.

EXAMPLE 22 (Method 4H) 2,6-Dichloro-4-nitrophenol

3,4,5-Trichloronitrobenzene (14.86 g) is added to a solution ofpotassium phenoxide (8.66 g) in diethylene glycol (66 mL) and themixture is heated to 160° C. for approximately 15 hours. The resultingdark brown solution is cooled to room temperature, poured onto 100 mLcold water, and extracted twice with diethyl ether. The pooled organicextracts are washed with water, 10% aqueous sodium hydroxide, and thendried over anhydrous magnesium sulfate. Following removal of the solventunder reduced pressure the resulting oil is distilled in a Kugelrohrapparatus to provide a yellow oil that solidifies on standing.Recrystallization from ethanol-water provides the desired product as apale yellow solid.

EXAMPLE 23 (Method 5A) (3,5-Dichloro-4-ethoxy-phenyl)-carbamic AcidTert-butyl Ester

To a solution of (3,5-dichloro-4-hydroxy-phenyl)-carbamic acidtert-butyl ester (1.0 g) and potassium carbonate (1.0 g) in acetone (18mL) is added ethyl iodide (0.36 mL) and the mixture is stirred forapproximately 15 hours at room temperature. The solution is thenfiltered, concentrated under reduced pressure, and partitioned betweenethyl acetate and water. The separated aqueous layer is furtherextracted twice with ethyl acetate, and the pooled organic extracts arewashed successively with 10% aqueous sodium hydroxide, with water, andthen dried over anhydrous sodium sulfate. Evaporation of the solventunder reduced pressure gave the desired product as a tan solid.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

(3,5-Dichloro-4-ethoxy-phenyl)-carbamic acid tert-butyl ester

(4-Butoxy-3,5-dichloro-phenyl)-carbamic acid tert-butyl ester

(4-Benzyloxy-3,5-dichloro-phenyl)-carbamic acid tert-butyl ester

(4-Carbamoylmethoxy-3,5-dichloro-phenyl)-carbamic acid tert-butyl ester

[3,5-Dichloro-4-(2-nitrilo-ethoxy)-phenyl]-carbamic acid tert-butylester

(4-tert-Butoxycarbonylamino-2,6-dichloro-phenoxy)-acetic acid methylester

3-Butoxy-benzoic acid methyl ester

3-tert-Butoxycarbonylmethoxy-benzoic acid methyl ester

3-Carbamoylmethoxy-benzoic acid methyl ester

[4-(3-Carbamoylmethoxy-benzoylamino)-phenyl]-carbamic acid tert-butylester

{4-[3-(2-Chloro-ethoxy)-benzoylamino]-phenyl}-carbamic acid tert-butylester

EXAMPLE 24 (Method 5C) (2,6-Dichloro-4-nitro-phenoxy)-acetic acidtert-butyl ester

To a solution of 2,6-dichloro-4-nitrophenol (2.5 g) and potassiumcarbonate (3.3 g) in dimethyl-formamide (50 mL) is addedtert-butyl-bromoacetate (10 mL) and the mixture is stirred at roomtemperature for two days. The solution is then poured into 500 mL water,extracted three times with hexanes, and the pooled organic extracts arewashed with saturated aqueous ammonium chloride and then dried overanhydrous magnesium sulfate. Evaporation of the solvent under reducedpressure followed by trituration of the resulting oil with hexanesprovides the desired product as a white solid.

Using the above procedure and starting materials the following compoundswere prepared:

3-Dimethylamino-1-(4-nitro-phenyl)-propenone

2-Chloro-1-isopropoxy-4-nitro-benzene

1,3-Dichloro-2-methoxy-4-methyl-5-nitro-benzene

1-Chloro-4-ethoxy-2-methoxy-5-nitro-benzene

1-Butoxy-4-chloro-5-methoxy-2-nitro-benzene

1-Chloro-2-methoxy-5-nitro-4-(phenylmethoxy)benzene (CA name)

1-Chloro-4-methoxy-5-nitro-2-(phenylmethoxy)benzene (CA name)

(2,6-Dichloro-4-nitro-phenoxy)-acetic acid tert-butyl ester

(2,6-Dichloro-4-nitro-phenoxy)-acetonitrile

1-Chloro-4-methoxy-2-methyl-5-nitro-benzene

2-(4-Chloro-5-methoxy-2-nitro-phenoxy)-acetamide

2-(2-Chloro-5-methoxy-4-nitro-phenoxy)-acetamide

(4-Chloro-5-methoxy-2-nitro-phenoxy)-acetonitrile

(2-Chloro-5-methoxy-4-nitro-phenoxy)-acetonitrile

4-(2-Chloro-5-methoxy-4-nitro-phenoxy)-butyronitrile

2-(4-Chloro-5-methoxy-2-nitro-phenoxy)-ethanol

2-(2-Chloro-5-methoxy-4-nitro-phenoxy)-ethanol

(2-Chloro-5-methoxy-4-nitro-phenoxy)-acetic acid tert-butyl ester

(2-Chloro-5-methoxy-4-nitro-phenoxy)-acetic acid methyl ester

(4-Chloro-5-methoxy-2-nitro-phenoxy)-acetic acid methyl ester

(4-Chloro-5-methoxy-2-nitro-phenoxy)-acetic acid tert-butyl ester

(2-Chloro-4-nitro-phenoxy)-acetonitrile

1-Butoxy-2-chloro-4-nitro-benzene

2-Chloro-4-nitro-1-(2,2,2-trifluoro-ethoxy)-benzene

2-Chloro-4-nitro-1-propoxy-benzene

2-Chloro-1-ethoxy-4-nitro-benzene

1,3-Diiodo-2,4-dimethoxy-5-nitro-benzene

1,3-Dibromo-2,4-dimethoxy-5-nitro-benzene

3-Chloro-2,4-dimethoxy-nitrobenzene

EXAMPLE 25 (Method 5E)[3,5-Dichloro-4-(2-hydroxy-ethoxy)-phenyl]-carbamic Acid Tert-butylEster

To a solution of (3,5-dichloro-4-hydroxy-phenyl)-carbamic acidtert-butyl ester (1.0 g) and potassium carbonate (0.55 g) in toluene (20mL) is added ethylene carbonate (1.6 g) and the mixture is heated toreflux for 3 hours. To the cooled reaction mixture is added 2.5 Maqueous sodium hydroxide (50 mL), and the separated organic layer isthen washed successively with water, then saturated aqueous sodiumchloride, and then dried over anhydrous sodium sulfate. The solvent isthen removed by evaporation under reduced pressure and the resultingresidue is chromatographed over silica gel (30% ethyl acetate in hexanesis used as the eluant) to provide the desired product as a white foam.

EXAMPLE 26 (Method 6) 3-(2-Chloro-4-nitro-phenoxy)-1-methyl-pyrrolidine

To a solution of 2-chloro-4-nitrophenol (2.0 g) in tetrahydrofuran (60mL) is added 1-methyl-3-pyrrolidinol (2.3 g), triphenyl phosphine (6.0g), and diethylazo-dicarboxylate (3.6 mL) and the mixture is stirred atroom temperature under an atmosphere of argon for 1.5 hours. Thesolution is then concentrated under reduced pressure, diluted with ethylacetate, washed successively with 10% aqueous sodium hydroxide, water,saturated aqueous sodium chloride, and dried over anhydrous magnesiumsulfate. The solvent is removed by evaporation under reduced pressureand the residue is chromatographed over silica gel (ethyl acetate then10% methanol in dichloromethane is used as the eluant). Pooled productfractions are then recrystallized from hexanes to provide the desiredproduct as a yellow solid.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

4-(2-Chloro-4-nitro-phenoxy)-1-methyl-piperidine

3-(2-Chloro-4-nitro-phenoxy)-1-methyl-pyrrolidine

[2-(2-Chloro-4-nitro-phenoxy)-ethyl]-dimethyl-amine

[3-(2-Chloro-4-nitro-phenoxy)-propyl]-dimethyl-amine

EXAMPLE 27 (Method 7A) 2-Chloro-3-methoxy-6-nitro-phenol and2,4-Dichloro-3-methoxy-6-nitro-phenol

To a flask containing 3-methoxy-6-nitro-phenol (0.5 g) is added aqueoussodium hypochlorite (5.25% aqueous solution, 21 mL) and the mixture isstirred at room temperature for approximately 24 hours. The mixture isthen cooled in an ice-bath, acidified by addition of concentratedhydrochloric acid, then extracted twice with ethyl acetate. Theseorganic extracts are dried over anhydrous magnesium sulfate, the solventis removed by evaporation under reduced pressure, and the residue ischromatographed over silca gel (15% acetone in hexanes is used as theeluant) to provide both the mono- and di-chlorinated products as yellowsolids.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

3-Chloro-2-hydroxy-4-methoxy-nitrobenzene

3,5-Dichloro-2-hydroxy-4-methoxy-nitrobenzene

EXAMPLE 28 (Method 7B) 2,4-Dichloro-3-methyl-6-nitro-phenol

To a solution of 3-methyl-4-nitro-phenol (5.0 g) in water (150 mL) isadded aqueous sodium hypochlorite (5.25% aqueous solution, 230 mL) andthe mixture is stirred at room temperature for approximately 15 hours.Additional aqueous sodium hypochlorite (5.25% aqueous solution, 230 mL)is added and the mixture is permitted to stir at room temperature for2.5 days. The mixture is then cooled in an ice-bath, acidified byaddition of concentrated hydrochloric acid, then extracted twice withethyl acetate. These organic extracts are dried over anhydrous magnesiumsulfate, the solvent is removed by evaporation under reduced pressure,and the residue is chromatographed over silca gel (ethyl acetate is usedas the eluant) to provide the desired product as a yellow solid. Ananalytically pure sample is obtained by a single recrystallization fromchloroform.

EXAMPLE 29 (Method 7C) 1-Bromo-2,4-dimethoxy-5-nitro-benzene

To a solution of 2,4-dimethoxy-nitrobenzene (0.50 g) in chloroform (3mL) is added dropwise a solution of bromine (0.23 g) in chloroform (1mL) and the mixture is allowed to stir at room temperature forapproximately 15 hours. Additional bromine (0.15 g) in chloroform (1 mL)is added and the reaction is stirred for an additional 4 hours. Themixture is then poured onto 5% aqueous sodium bisulfite and thenextracted with chloroform. Pooled organic extracts are then washedsuccessively with 5% aqueous sodium bisulfite then saturated sodiumchloride, and then dried over anhydrous sodium sulfate. Removal of thesolvent under reduced pressure and recrystallization of the residue fromtoluene provides the desired product as a yellow solid.

EXAMPLE 30 (Method 7D) 2,4-Dibromo-3-methoxy-6-nitro-phenol

To a solution of 5-methoxy-2-nitro-phenol (0.25 g) and silvertrifluoroacetate (0.49 g) in glacial acetic acid (3 mL) is addeddropwise a solution of bromine (1.42 g) in glacial acetic acid (3 mL)and the mixture is stirred at room temperature for approximately 24hours. The solution is then partitioned between ethyl acetate and water,and the organic layer is washed successively three times with 5% aqueoussodium bisulfite, three times with saturated aqueous sodium bicarbonate,and once with saturated aqueous sodium chloride. The organic layer isthen dried over anhydrous magnesium sulfate and the solvent is removedunder reduced pressure. The residue is chromatographed over silica gel(20% ethyl acetate in hexanes is used as the eluant) then recrystallizedfrom chloroform to provide the desired dibrominated product as an orangesolid.

EXAMPLE 31 (Method 7E) 1 -Iodo-2,4-dimethoxy-5-nitro-benzene

To a solution of 2,4-dimethoxy-nitrobenzene (1.0 g) in glacial aceticacid (30 mL) is added benzyltrimethylammonium dichloroiodate (1.90 g)and anhydrous zinc chloride (1.0 g) and the mixture is stirred at roomtemperature under an atmosphere of argon. Additionalbenzyltrimethylammonium dichloroiodate (0.4 g) is added after 5 hoursand again after 24 hours. Additional zinc chloride (0.5 g) and glacialacetic acid (15 mL) is added after 24 hours. The mixture is permitted tostir at room temperature for 3 days and is then filtered, diluted with5% aqueous sodium bisulfite, and extracted three times with ethylacetate. These pooled organic extracts are washed successively with 5%aqueous sodium bisulfite, saturated aqueous sodium chloride, then driedover anhydrous magnesium sulfate. After removal of the solvent underreduced pressure the residue is triturated with hexanes to provide thedesired product as a pale yellow solid.

EXAMPLE 32 (Method 7F) 2,4-Diiodo-3-methoxy-6-nitro-phenol

To a solution of 5-methoxy-2-nitro-phenol (0.25 g) in dichloromethane(15 mL) and methanol (6 mL) is added benzyltrimethylammoniumdichloroiodate (1.08 g) and sodium bicarbonate (0.85 g) and the mixtureis allowed to stir at room temperature for 24 hours. The solution isthen filtered, the filtrate is concentrated under reduced pressure, theresidue is dissolved in ethyl acetate and then washed successively with5% aqueous sodium bicarbonate, 5% aqueous sodium bisulfite, andsaturated aqueous sodium chloride. After drying over anhydrous magnesiumsulfate the solvent is removed by evaporation under reduced pressure andthe residue is recrystallized from toluene to provide the desiredproduct as yellow needles.

EXAMPLE 33 (Method 7G) 1-Fluoro-2,4-dimethoxy-5-nitro-benzene

To a solution of 2,4-dimethoxy-nitrobenzene (1.0 g) in tetrachloroethane(10 mL) is added 3,5-dichloro-l-fluoro-pyridinium triflate (85%, 5.07 g)and the mixture is heated to 120° C. for 5 hours. Additional3,5-dichloro-l-fluoro-pyridinium triflate (85%, 0.25 g) is added andheating is continued for 1 hour. The solution is then cooled to roomtemperature and passed over a column of silica gel (hexanes followed by30% ethyl acetate in hexanes is used as the eluant). Product containingfractions are combined, evaporated under reduced pressure, and theresidue is crystallized from hexanes to provide the desired product as atan solid.

EXAMPLE 34 (Method 8) 3-Chloro-4-trifluoromethyl-nitrobenzene

A solution of 3-chloro-4-iodo-nitrobenzene (2.26 g),trimethyl(trifluoromethyl)silane (5.68 g), copper(I) iodide (2.28 g),and potassium fluoride (0.56 g) in N,N-dimethylformamide (8 mL) isheated in a sealed tube to 80° C. for 40 hours. The solution is thencooled, diluted with diethyl ether, filtered through diatomaceous earth,and the filtrate is washed successively with water, saturated aqueoussodium chloride, and then dried over anhydrous sodium sulfate. Thesolvent is removed under reduced pressure and the residue ischromatographed over silica gel (1% diethyl ether in hexanes followed by10% ethyl acetate in hexanes is used as the eluant) to provided thedesired product as a colorless oil.

EXAMPLE 35 (Method 9) (3-Chloro-4-methanesulfinyl-phenyl)-carbamic AcidTert-butyl Ester

To a solution of (3-chloro-4-thiomethyl-phenyl)-carbamic acid tert-butylester (0.89 g) in dichloromethane (15 mL) at 0° C. is added a solutionof dimethyldioxirane (0.11 M in acetone, 34 mL) and the mixture isstirred at 0° C. for 1 hour. The solvent is removed under reducedpressure and the residue is dissolved in dichloromethane, washed withsaturated aqueous sodium chloride, and then dried over anhydrousmagnesium sulfate. Removal of the solvent under reduced pressure gavethe desired product as an orange foam.

EXAMPLE 36 (Method 9B)[4-(2-Methylsulfinyl-benzoylamino)-phenyl]-carbamic Acid Tert-butylEster

To a solution of2-methylsulfanyl-N-[4-(2,2,2-trifluoro-acetylamino)-phenyl]-benzamide(234 mg) is added a saturated solution of sodium periodate (5 mL) andthe mixture is stirred for 12 hours. The purple mixture is poured intowater, extracted with ethyl acetate, dried over anhydrous potassiumcarbonate and evaporated to yield a red solid, 101 mg.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[4-(2-Methanesulfinyl-benzoylamino)-phenyl]-carbamic acid tert-butylester

2-Methanesulfinyl-N-[4-(2,2,2-trifluoro-acetylamino)-phenyl]-benzamide

EXAMPLE 37 (Method 10) (3-Chloro-4-methanesulfonyl-phenyl)-carbamic AcidTert-butyl Ester

To a solution of (3-chloro-4-thiomethyl-phenyl)-carbamic acid tert-butylester (0.90 g) in dichloromethane (30 mL) at 0° C. is added a solutionof dimethyldioxirane (0.11 M in acetone, 80 mL) and the mixture isstirred at 0° C. for 1 hour. The solvent is removed under reducedpressure and the residue is dissolved in dichloromethane, washed withsaturated aqueous sodium chloride, and then dried over anhydrousmagnesium sulfate. Removal of the solvent under reduced pressure givesthe desired product as an orange foam.

EXAMPLE 38 (Method 11) 3-Chloro-4-vinyl-phenylamine

To a deoxygenated solution of 3-chloro-4-iodo-aniline (6.95 g),triphenyl arsine (0.67 g), and tris(dibenzylideneacetone)palladium(O)(0.50 g) in tetrahydrofuran (120 mL) at 50° C. is added tributylvinyltin(10 g) and the mixture is stirred for approximately 15 hours at 50° C.under an atmosphere of argon. The reaction is then cooled, filteredthrough diatomaceous earth, and the filtrate is evaporated to drynessunder reduced pressure. The residue is dissolved in hexanes and thenextracted three times with 5% aqueous hydrochloric acid. These aqueousacidic extracts are then basified with solid potassium carbonate andextracted three times with ethyl acetate. These pooled organic extractsare then washed with saturated aqueous sodium chloride, dried overanhydrous magnesium sulfate, and the solvent is removed under reducedpressure. The resulting residue is chromatographed over silica gel(hexanes and then 10% ethyl acetate in hexanes is used as the eluant) toprovide the desired product as an amber oil.

EXAMPLE 39 (Method 12) [3-Chloro-4-(1-hydroxy-ethyl)-phenyl]-carbamicAcid 2-trimethylsilanyl-ethyl Ester

(3-Chloro-4-vinyl-phenyl)-carbamic acid 2-trimethylsilanyl-ethyl ester(2.6 g) is added to a solution of mercuric acetate (3.48 g) in water (7mL) and tetrahydrofuran (5.25 mL) and the mixture is stirred forapproximately 15 hours. 3N Aqueous sodium hydroxide (8.7 mL) and a 0.5 Msolution of sodium borohydride in 3N aqueous sodium hydroxide (8.7 mL)are then added and stirring is continued for 6 hours. The solution isthen saturated with sodium chloride and extracted with ethyl acetate.These organic extracts are then washed with saturated aqueous sodiumchloride and dried over anhydrous sodium sulfate. Following removal ofthe solvent under reduced pressure the residue is chromatographed oversilica gel (20% ethyl acetate in hexanes is used as the eluant) toprovide the desired product as a white solid.

EXAMPLE 40 (Method 13) [3-Chloro-4-(2-hydroxy-ethyl)-phenyl]-carbamicAcid Tert-butyl Ester

To a stirring suspension of sodium borohydride (0.45 g) intetrahydrofuran (13 mL) at 0° C. is added glacial acetic acid (0.75 mL)and the mixture is stirred at 0° C. for 1 hour. The solution is thenwarmed to room temperature and (3-chloro-4-vinyl-phenyl)-carbamic acid2-trimethylsilanyl-ethyl ester (1.0 g) is added. The reaction is stirredat room temperature for approximately 15 hours and then heated to refluxfor approximately 20 hours. The mixture is then cooled and solutions of5 N aqueous sodium hydroxide (0.80 mL) and 30% aqueous hydrogen peroxide(0.56 mL) are added. After stirring for an additional 15 hours thelayers are separated, the aqueous layer is extracted three times withdiethyl ether, and these organic extracts are dried over anhydrousmagnesium sulfate. Following removal of the solvent under reducedpressure the residue is chromatographed over silica gel (40% ethylacetate in hexanes is used as the eluant) to provide the desired productas an amber oil.

EXAMPLE 41 (Method 14) [4-(1-Azido-ethyl)-3-chloro-phenyl]-carbamic Acid2-trimethylsilanyl-ethyl Ester

To a solution of [3-chloro-4-(1-hydroxy-ethyl)-phenyl]-carbamic acid2-trimethylsilanyl-ethyl ester (1.25 g) in tetrahydrofuran (20 mL) at 0°C. under an atmosphere of argon is added triphenyl-phosphine (2.6 g),hydrazoic acid (approximately 2.5 molar equivalents in dichloromethane,prepared by the method of Fieser and Fieser, Reagents for OrganicSynthesis, Vol. 1, pg. 446; Wiley, New York) and diethylazodicarboxylate (1.72 g). After approximately 10 minutes the solvent isremoved under reduced pressure and the residue is chromatographed oversilica gel (5% ethyl acetate in hexanes is used as the eluant) toprovide the desired product as a colorless oil.

EXAMPLE 42 (Method 15)[3-Chloro-4-(3-dimethylamino-prop-1-ynyl)-phenyl]-carbamic AcidTert-butyl Ester

To a deoxygenated solution of (3-chloro-4-iodo-phenyl)-carbamic acidtert-butyl ester (10.0 g) in triethylamine (120 ml) is added1-dimethylamino-2-propyne (2.82 g),bis(triphenyl-phosphine)palladium(II) chloride (0.4 g), and cuprousiodide (0.054 g). The mixture is stirred at room temperature under anatmosphere of argon for approximately 6 hours and is then heated briefly(ca. 10 minutes) to 60° C. The reaction mixture is then cooled, filteredthrough diatomaceous earth, and the solvent is removed by evaporationunder reduced pressure. The residue is dissolved in ethyl acetate,washed three times with water, once with saturated aqueous sodiumchloride, and dried over anhydrous magnesium sulfate. The solvent isremoved by evaporation under reduced pressure, and the residue ischromatographed over silica gel (80% ethyl acetate in hexanes is used asthe eluant) to give the purified product as an amber oil that solidifiedon standing.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[3-Chloro-4-(3-dimethylamino-prop-1-ynyl)-phenyl]-carbamic acidtert-butyl ester

[3-(4-Methoxy-phenyl)-prop-2-ynyl]-dimethyl-amine

4-(3-Dimethylamino-prop-1-ynyl)-benzonitrile

Dimethyl-[3-(4-nitro-phenyl)-prop-2-ynyl]-amine

EXAMPLE 43 (Method 16)[3-Chloro-4-(3-dimethylamino-acryloyl)-phenyl]-carbamic Acid Tert-butylEster

To an ice cold solution of[3-chloro-4-(3-dimethylamino-prop-1-ynyl)-phenyl]-carbamic acidtert-butyl ester (4.0 g) in dichloromethane (30 ml) is added in smallportions 3-chloroperoxybenzoic acid (2.34 g). After the reaction isstirred at 0° C. for 20 minutes, the mixture is passed over twentyweight equivalents of basic alumina (Brockmann Grade I, 150 mesh) andthe N-oxide is eluted using a solution of 5% methanol indichloromethane. All fractions containing the desired amine N-oxide werecombined and evaporated to near dryness under reduced pressure. Theresidue is treated successively three times with small portions ofmethanol (ca. 50 ml) followed by evaporation to near dryness underreduced pressure, and the volume of the solution is adjusted to 250 mLby addition of methanol. The methanolic solution of the N-oxide is thenheated to reflux for approximately 15 hours, then cooled, and thesolvent is evaporated to dryness under reduced pressure. The residue ispurified by chromatography over silica gel (80% ethyl acetate in hexanesis used as the eluant) to give the desired product as a pale yellowsolid.

EXAMPLE 44 (Method 17) (3-Chloro-4-isoxazol-5-yl-phenyl)-carbamic AcidTert-butyl Ester

A solution of [3-chloro-4-(3-dimethylamino-acryloyl)-phenyl]-carbamicacid tert-butyl ester (270 mg) in dioxane (3 ml) is treated withhydroxylamine hydrochloride (122 mg) and the mixture is stirred at roomtemperature for 10 days. The mixture is diluted with ethyl acetate,washed successively with water, 5% aqueous sodium bicarbonate, saturatedaqueous sodium chloride, and then dried over anhydrous magnesiumsulfate. The solvent is removed by evaporation under reduced pressureand the resulting residue is chromatographed over silica gel (33% ethylacetate in hexanes is used as the eluant) to provide the desired productas a colorless solid.

EXAMPLE 45 (Method 18) [3-Chloro-4-(1H-pyrazol-3-yl)-phenyl]-carbamicacid tert-butyl ester

A solution of [3-chloro-4-(3-dimethylamino-acryloyl)-phenyl]-carbamicacid tert-butyl ester (250 mg) in ethanol (1.25 ml) is treated withhydrazine hydrate (0.25 ml) and the mixture is stirred at roomtemperature for 3 hours. The mixture is then diluted with 30 mL ofdiethyl ether, washed three times with water, once with saturatedaqueous sodium chloride, and dried over anhydrous magnesium sulfate. Thesolvent is removed by evaporation under reduced pressure and theresulting residue is chromatographed over silica gel (67% ethyl acetatein hexanes is used as the eluant) to provide the desired product as anoil.

EXAMPLE 46 (Method 19A)N-(2-Chloro-4-nitrophenyl)-2-thiomorpholino-4-yl-acetamide

To a solution N-(chloroacetyl)-2-chloro-4-nitroaniline (3.80 g) intetrahydrofuran (50 mL) is added thiomorpholine (10 mL) and the solutionallowed to stand for 1 hour. This reaction mixture is poured into watera pale yellow solid is collected and then recrystallized from hot2-propanol to give a pale yellow crystalline solid.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

(4-{2-[Bis-(2-hydroxy-ethyl)-amino]-acetylamino}-phenyl)-carbamic acidtert-butyl ester

[4-(2-Dimethylamino-acetylamino)-phenyl]-carbamic acid tert-butyl ester

{4-[3-(2-Dimethylamino-ethoxy)-benzoylamino]-phenyl}-carbamic acidtert-butyl ester

{4-[3-(2-Morpholin-4-yl-ethoxy)-benzoylamino]-phenyl )-carbamic acidtert-butyl ester

N-(2-Chloro-4-nitro-phenyl)-2-dimethylamino-acetamide

N-(2-Chloro-4-nitro-phenyl)-2-piperidin-1-yl-acetamide

N-(2-Chloro-4-nitro-phenyl)-2-morpholin-4-yl-acetamide

N-(2-Chloro-4-nitro-phenyl)-2-dipropylamino-acetamide

N-(2-Chloro-4-nitro-phenyl)-2-thiomorpholin-4-yl-acetamide

N-(2-Chloro-4-nitro-phenyl)-2-diethylamino-acetamide

N-(2-Chloro-4-nitro-phenyl)-2-pyrrolidin-1-yl-acetamide

2-Azepan-1-yl-N-(2-chloro-4-nitro-phenyl)-acetamide

N-(2-Chloro-4-nitro-phenyl)-2-(2-methyl-piperidin-1-yl)-acetamide

N-(2-Chloro-4-nitro-phenyl)-2-(3-methyl-piperidin-1-yl)-acetamide

N-(2-Chloro-4-nitro-phenyl)-2-(4-methyl-piperidin-1-yl)-acetamide

EXAMPLE 47 (Method 19B)N-(2-Chloro-4-nitrophenyl)-2-(2-dimethylaminoethylsulfanyl)acetamide

To a solution of N-(chloroacetyl)-2-chloro-4-nitroaniline (3.01 g) inN,N-dimethylformamide (100 mL) is added powdered sodium carbonate (6.0g) and 2-dimethylaminoethanethiol hydrochloride (6.0 g). The mixture isstirred for 1 hour at 25° C., poured into water and extracted into ethylacetate. The ethyl acetate solution is dried over anhydrous potassiumcarbonate and concentrated under reduced pressure to give an oil. Theoil is crystallized from toluene-hexanes (3:1) to yield a pale yellowcrystalline solid.

EXAMPLE 48 (Method 20)(4-tert-butoxycarbonylamino-2-chloro-phenyl)-carbamic Acid2-piperidin-1-yl-ethyl Ester

To a suspension of 1,1-carbonyl-di-(1,2,4)-triazole (4.0 g) indichloromethane (40 mL) is added a solution of (4-amino-3-chloro-phenyl)carbamic acid tert-butyl ester (5.0 g) in dichloromethane (45 mL)dropwise over 20 minutes. The reaction is stirred at room temperaturefor 30 minutes at which point a precipitate forms. To this mixture isadded piperidineethanol (6.6 mL) and tetra-hydrofuran (20 mL) is addedto maintain homogeneity. After heating at reflux overnight the reactionis cooled and then poured into water, the organic layer separated andthen washed with saturated aqueous sodium chloride. The solution isdried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure to a crude oil that is purified by chromatography oversilica gel (5% methanol in dichloromethane is used as the eluant) togive the desired product as a white foam.

EXAMPLE 49 5-Phenyl-[1,2,3]thiadiazole-4-carboxylic Acid Methyl Ester

A solution of ethyl benzoylacetate (1.1 g) in acetonitrile (10 mL) istreated with 4-methylbenzenesulfonyl azide (1.3 g) and triethylamine(1.6 g). After stirring overnight at room temperature, the reaction isconcentrated under reduced pressure and the resulting crude product isdissolved in ethyl acetate and washed with IN sodium hydroxide. Theorganic layer is then dried over anhydrous magnesium sulfate, filteredand concentrated under reduced pressure to yield a yellow oil. This oilis taken into dichloromethane and filtered through a pad of hydrousmagnesium silicate, eluting with dichloromethane to give the partiallypurified diazoketone as a colorless oil. A sample of the diazoketonefrom above (1.2 g) is dissolved in toluene (25 mL) and treated with2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (2.8g) and the reaction is heated to reflux. After 3 hours, the reaction iscooled to room temperature, loaded onto a pad of silica gel and elutedwith dichloromethane. After removing the solvent under reduced pressure,the resulting oil is purified by chromatography over silica gel (30%diethyl ether in petroleum ether is used as the eluant) and thenrecrystallized from hexanes to give the desired product as pale yellowneedles.

Using the above procedure and appropriate starting materials thefollowing compound was prepared:

5-Phenyl-[1,2,3]thiadiazole-4-carboxylic acid ethyl ester

5-Methyl-[1,2,3]thiadiazole-4-carboxylic acid methyl ester

EXAMPLE 50 Ethyl Benzoylacetate Semicarbazide

Ethyl benzoylacetate (5.0 g) is dissolved in methanol (10 mL) and addedrapidly to a hot solution of semicarbazide hydrochloride (29 g) in water(130 mL). To this is added pyridine (4.1 g) and after heating to refluxfor 5 minutes, the reaction mixture is cooled to −20° C. overnight. Theresulting solid semicarbazone is collected by filtration, washed withwater and then diethyl ether to give the desired product as whitecrystals.

Using the above procedure and appropriate starting materials thefollowing compound was prepared:

Ethyl (Z)-3-[(aminocarbonyl)hydrazono]-4,4,4-trifluorobutanoate

3-[(Z)-2-(Aminocarbonyl)hydrazono]-3-phenylpropanoic acid ethyl ester

3-[(E)-2-(Aminocarbonyl)hydrazono]-3-(3-furyl)propanoic acid ethyl ster

EXAMPLE 51 5-Phenyl-[1,2,3]thiadiazole-5-carboxylic Acid Ethyl Ester

A solution of ethyl benzoylacetate semicarbazone (2.5 g) in neat thionylchloride (5 mL) is stirred at 0° C. for 1 hour. Dichloromethane is thenadded (25 mL), the excess thionyl chloride is destroyed slowly withsaturated aqueous sodium bicarbonate. The precipitate which forms onquenching is removed by filtration and the filtrate is extracted withdichloromethane. Pooled organic extracts are dried over anhydrousmagnesium sulfate, filtered and concentrated under reduced pressure.Chromatography over silica gel (50% hexanes in dichloromethane is usedas the eluant) affords the desired product as a colorless oil.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid methyl ester

4-Phenyl-[1,2,3]thiadiazole-5-carboxylic acid ethyl ester

4-Furan-3-yl-[1,2,3]thiadiazole-5-carboxylic acid ethyl ester

EXAMPLE 52 4-Methyl-[1,2,3]thiadiazole-5-carboxylic Acid

4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid methyl ester (1.7 g) isdissolved in methanol (15 mL) and treated with 1N sodium hydroxide (16mL). After stirring at room temperature for 1 hour, the reaction istreated with concentrated hydrochloric acid (1.5 mL) and concentratedunder reduced pressure. The resulting turbid aqueous layer is extractedtwice with diethyl ether and the pooled organic layers are dried overanhydrous magnesium sulfate, filtered and concentrated under reducedpressure to give the desired compound as a white powder.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

3-Ethoxycarbonylmethoxy-benzoic acid

5-Furan-3-yl-[1,2,3]thiadiazole-4-carboxylic acid

Thiazole-4-carboxylic acid

4-Methyl-[,2,3]thiadiazole-5-carboxylic acid

5-Methyl-[1,2,3]thiadiazole-4-carboxylic acid

EXAMPLE 53 (Method 25) Trifluoro-methanesulfonic Acid4-chloro-5-methoxy-2-nitro-phenyl Ester

To a solution of 4-chloro-5-methoxy-2-nitro-phenol (6.5 g) indichloromethane (150 mL) at 0° C. under an atmosphere of argon is addedtriethylamine (10 g) and then a solution of trifluoro-methanesulfonicanhydride (13.5 g) in dichloromethane (30 mL). The solution is stirredat 0° C. for 10 minutes, and is then diluted with dichloromethane andwashed successively with saturated aqueous sodium bicarbonate andsaturated aqueous sodium chloride. After drying over anhydrous sodiumsulfate the solvent is removed by evaporation under reduced pressure andthe residue is dissolved in a solution of 20% dichloromethane in hexanesand passed through a short column of hydrous magnesium silicate (20%dichloromethane in hexanes is used as the eluant). Product containingfractions are pooled and the solvents removed by evaporation underreduced pressure to give the desired product as a yellow oil.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

Trifluoro-methanesulfonic acid 4-chloro-5-methoxy-2-nitro-phenyl ester

Trifluoro-methanesulfonic acid 4-chloro-2-nitro-phenyl ester

Trifluoro-methanesulfonic acid 2-chloro-6-nitro-phenyl ester

EXAMPLE 54 (Method 26)[4-(3-Dimethylamino-benzoylamino)-phenyl]-carbamic Acid T-butyl Ester

A solution of [4-(3-amino-benzoylamino)-phenyl]-carbamic acid t-butylester (505 mg), sodium cyanoborohydride (250 mg), acetic acid (3 drops)and 40% aqueous formaldehyde (4 mL) in 1:2 tetrahydrofuran-methanol (15mL) is stirred for 15 minutes, and then poured into saturated aqueoussodium bicarbonate and extracted into ethyl acetate. The ethyl acetatesolution is dried over anhydrous potassium carbonate and concentratedunder reduced pressure to give a solid which is recrystallized fromacetonitrile to provide a pale pink crystalline solid.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[4-(3-Dimethylamino-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

(3-Bromo-5-trifluoromethyl-phenyl)-dimethyl-amine

N-(3-Chloro-5-dimethylamino-phenyl)-acetamide

EXAMPLE 55 (Method 27) N-(4-Aminophenyl)-2-hydroxybenzamide

To a solution of 2-(4-aminophenylcarbamoyl) phenyl acetate (580 mg) inmethanol (10 mL) is added saturated sodium bicarbonate (2 mL) and water(3 mL). The mixture is heated at 80° C. for 30 minutes, then poured intohalf-saturated aqueous sodium chloride and extracted with ethyl acetate.The ethyl acetate solution is dried over anhydrous sodium sulfate andconcentrated under reduced pressure to give an oil which is thentriturated with diethyl ether to provide the desired product as a whitesolid.

EXAMPLE 56 (Method 28) [4-(3-(Hydroxybenzoylamino)phenyl}carbamic AcidT-butyl Ester

To a solution of of 3-(4-aminophenylcarbamoyl) phenyl acetate (4.34 g)in methanol (75 mL) is added 0.1 N aqueous sodium hydroxide (25 mL) andtetrahydrofuran (25 mL). This solution is heated at 40° C. for 30minutes, then cooled, poured into 1 M hydrochloric acid and extractedwith ethyl acetate. The ethyl acetate solution is dried over anhydroussodium sulfate and concentrated under reduced pressure to give a whitesolid, which is further purified by trituration with diethyl ether.

EXAMPLE 57 (Method 29) N-(4-Aminophenyl)-2-hydroxymethylbenzamide

To a solution of N-(4-aminophenyl)phthalimide (332 mg) intetrahydrofuran (4 mL) is added lithium borohydride (1.0 g) and themixture is stirred for 1 hour at 25° C. The mixture is poured into waterand extracted into ethyl acetate. The ethyl acetate solution is driedover anhydrous sodium sulfate and concentrated under reduced pressure togive a white foam, which when triturated with diethyl ether provides thedesired product as a white powder.

EXAMPLE 58 (Method 30) (3-Chloro-5-dimethylamino-phenyl)-carbamic AcidTert-butyl Ester

To a solution of (3-amino-5-chloro-phenyl)-carbamic acid tert-butylester (0.32 g) in toluene (10 mL) is added aqueous formaldehyde (37%,1.5 mL) then 10% palladium on carbon (0.50 g) and the mixture is stirredunder an atmosphere of hydrogen for approximately 15 hours. The solutionis then filtered through diatomaceous earth and the filtrate isconcentrated under reduced pressure. The residue is chromatographed oversilica gel (50% dichloromethane in hexanes is used as the eluant) toprovide the desired product as a white solid.

EXAMPLE 59 (Method 35)N-(4{3-[3,5-Dichloro-4-(2-hydroxy-ethoxy)-phenyl]-thioureido}-phenyl)-acetamide

To a solution of acetic acid2-{4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-ethylester (0.16 g) in a 1:1 mixture of tetrahydrofuran and methanol (2.5 mL)is added 1N aqueous sodium hydroxide (1 mL) and the mixture is stirredfor approximately 2 hours at room temperature. The solution is thenpoured into 2 M aqueous hydrochloric acid (3 mL), extracted into ethylacetate, and the extracts are dried over anhydrous sodium sulfate. Thesolvent is removed by evaporation under reduced pressure and the residueis triturated with diethyl ether to provide the desired product as awhite solid.

EXAMPLE 60 (Method 36){4-[3-(4-Acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-aceticAcid

To a solution of{4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-aceticacid ethyl ester (0.29 g) in a 1:1 mixture of tetrahydrofuran andmethanol (4 mL) is added 1N aqueous sodium hydroxide (2 mL) and themixture is stirred for approximately 2 hours at room temperature. Thesolution is then poured into 2 M aqueous hydrochloric acid (5 mL),extracted into ethyl acetate, and the extracts are dried over anhydroussodium sulfate. The solvent is removed by evaporation under reducedpressure and the residue is triturated with diethyl ether to provide thedesired product as a white solid.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

{4-[3-(4-Acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-aceticacid

2-[3-(4-Acetylamino-phenyl)-thioureido]-4-chloro-5-methoxy-phenoxy}-aceticacid

{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-5-methoxy-phenoxy}-aceticacid

EXAMPLE 61 (Method 37) Benzoic acid2-{4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-ethylester

To an ice cooled solution ofN-(4-{3-[3,5-dichloro-4-(2-hydroxy-ethoxy)-phenyl]-thioureido}-phenyl)-acetamide(0.20 g) in pyridine (2 mL) and tetrahydrofuran (0.5 mL) is addedbenzoyl chloride (0.08 g) and the mixture is stirred at 0° C. for 1.5hours. The mixture is then diluted with ethyl acetate, washedsuccessively two times with 2% aqueous hydrochloric acid, once withsaturated aqueous sodium chloride, then dried over anhydrous sodiumsulfate. After removal of the solvent under reduced pressure the residueis chromatographed over silica gel (5% methanol in dichloromethane isused as the eluant) and product containing fractions are combined,evaporated under reduced pressure, and the residue is recrystallizedfrom acetone-hexanes to provide the desired product as a white powder.

EXAMPLE 62 (Method 38) Methanesulfonic Acid2-{4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-ethylEster

To an ice cooled solution ofN-(4-{3-[3,5-dichloro-4-(2-hydroxy-ethoxy)-phenyl]-thioureido}-phenyl)-acetamide(0.20 g) in pyridine (2 mL) and tetrahydrofuran (0.5 mL) is addedmethanesulfonyl chloride (0.11 g) and the solution is stirred at 0° C.for 45 minutes. The reaction mixture is then diluted with ethyl acetate,washed successively twice with 2% aqueous hydrochloric acid, once withsaturated aqueous sodium chloride, and then dried over anhydrousmagnesium sulfate. After removing the solvents by evaporation underreduced pressure the resulting residue is recrystallized fromacetone-hexanes to give the desired product as a white powder.

EXAMPLE 63 (Method 39)N-(4-{3-[3,5-Dichloro-4-(2-dimethylamino-ethoxy)-phenyl]-thioureido)-phenyl)-acetamide

To a solution of methanesulfonic acid2-{4-[3-(4-acetylamino-phenyl)-thioureido]- 2,6-dichlorophenoxy}-ethylester (0.33 g) in tetrahydrofuran (6 mL) is added aqueous dimethyl-amine(8.8 M, 0.5 mL) and the mixture is stirred at room temperature for 5days. The reaction mixture is then diluted with ethyl acetate, thenwashed with saturated aqueous sodium chloride and dried over anhydrousmagnesium sulfate. After removal of the solvent under reduced pressurethe residue is chromatographed over silica gel (pure methanol is used asthe eluant). Pooled product containing fractions are evaporated underreduced pressure and the residue is recrystallized from acetonitrile toprovide the desired product as a white powder.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

N-(4-{3-[3,5-Dichloro-4-(2-dimethylamino-ethoxy)-phenyl]-thioureido}-phenyl)-acetamide

Benzoic acid2-{4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-ethylester

EXAMPLE 64 (Method 40) Furan-2-carboxylic Acid(4-{3-[4-(1-amino-ethyl)-3-chloro-phenyl]-thioureido}-phenyl)-amide

To a solution of tin(II) chloride dihydrate (0.25 g) in methanol (2.5mL) is added furan-2-carboxylic acid(4-{3-[4-(1-azido-ethyl)-3-chloro-phenyl]-thioureido}-phenyl)-amide(0.22 g) and the solution is stirred for approximately 15 hours at roomtemperature. The solution is then diluted with ethyl acetate, washedsuccessively with saturated aqueous sodium bicarbonate then saturatedaqueous sodium chloride, then dried over anhydrous sodium sulfate. Afterremoval of the solvent by evaporation under reduced pressure the residueis chromatographed over silica gel (8% methanol in dichloro-methanecontaining 1% triethylamine is used as the eluant) to provide thedesired product as a yellow solid.

EXAMPLE 65 (Method 41) [1,2,3]Thiadiazole-4-carboxylic Acid(4-isothiocyanato-phenyl)-amide

To a ice cooled solution of 1,1′-thiocarbonyldiimidazole (7.28 g) intetrahydrofuran (50 mL) is added [1,2,3]-thiadiazole-4-carboxylic acid(4-amino-phenyl) amide (9.0 g) in tetrahydrofuran (100 mL). Afterapproximately one hour the solvent is removed by evaporation and theresidue is dissolved in ethyl acetate. Diethyl ether is added toprecipitate the crude product, which is then collected by filtration,dissolved in dichloromethane, and passed through a plug of hydrousmagnesium silicate. After removal of solvents, the residue isrecrystallized from ethyl acetate-hexanes to provide the desired productas a slightly yellow solid.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

2-Fluoro-N-(4-isothiocyanato-phenyl)-benzamide

Furan-2-carboxylic acid (4-isothiocyanato-phenyl)-amide

[1,2,3]Thiadiazole-4-carboxylic acid (4-isothiocyanato-phenyl)-amide

Thiazole-4-carboxylic acid (4-isothiocyanato-phenyl)-amide

EXAMPLE 66 (Method 42)N,N-Dimethyl-5-trifluoromethyl-benzene-1,3-diamine

To a solution of 3-amino-5-bromo-benzotrifluoride (1.0 g) in degassed(argon) tetrahydrofuran (2 mL) is addedbis-(tri-o-tolylphosphino)palladium (0.15 g), a solution ofdimethylamine in tetra-hydrofuran (2M, 4.2 mL), and a solution oflithium bis(trimethylsilyl)amide in tetrahydrofuran (1M, 10.4 mL). Thereaction mixture is heated in a sealed vessel to 100° C. forapproximately 2.5 hours to complete the reaction. The mixture is thencooled to room temperature, quenched by addition of water, and dilutedwith ethyl acetate. The product is extracted three times into 5% aqueoushydrochloric acid, and pooled acidic extracts are then basified withcooling by addition of 5N aqueous sodium hydroxide. This basic solutionis then extracted with ethyl acetate, and these pooled organic extractsare washed with saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate, and evaporated to dryness under reduced pressure. Theresulting residue is chromatographed over silica gel (20-30% ethylacetate in hexanes is used as the eluant) to provide the desired productas a slightly tinted solid.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

3-(4-Methyl-piperazin-1-yl)-5-trifluoromethyl-phenylamine

3-Morpholin-4-yl-5-trifluoromethyl-phenylamine

3-Piperidin-1-yl-5-trifluoromethyl-phenylamine

3-Pyrrolidin-1-yl-5-trifluoromethyl-phenylamine

N,N-Dimethyl-5-trifluoromethyl-benzene-1,3-diamine

N-Isobutyl-N-methyl-5-trifluoromethyl-benzene-1,3-diamine

N-Butyl-N-methyl-5-trifluoromethyl-benzene-1,3-diamine

EXAMPLE 67 (Method 43) (3-Isobutyl-5-trifluoromethyl-phenyl)-carbamicAcid Tert-butyl Ester

To a sealed tube containing tetrahydrofuran (5 mL) that is capped with arubber septum and cooled in a dry ice-acetone bath is bubbledisobutylene for about 5 minutes. A solution of9-borabicyclo[3.3.1]nonane in tetrahydrofuran (0.5 M, 11 mL) is added,the vessel is sealed with a teflon cap, slowly warmed to roomtemperature and kept at room temperature for approximately 2.5 hours.The mixture is then re-cooled in a dry ice-acetone bath, the teflon capis replaced by a rubber septum, and argon is bubbled through the mixturewith venting to removed the excess isobutylene. A solution of(3-bromo-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (1.7g) in tetrahydrofuran (12 mL) is added, followed by[1,1′-bis(diphenylphosphino)-ferrocene]palladium(II)chloride-dichlormethane complex (0.12 g), and then 3N aqueous sodiumhydroxide. The vessel is again sealed with the teflon cap and is thenheated to 65° C. for approximately 15 hours. The mixture is then cooledto room temperature, diluted with hexanes, washed with water, saturatedaqueous sodium chloride, dried over anhydrous magnesium sulfate, andevaporated under reduced pressure. The resulting oil is chromatographedover silica gel (5% ethyl acetate in hexanes is used as the eluant) toprovide the desired product as a white powder.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[3-(2-Methyl-butyl)-5-trifluoromethyl-phenyl]-carbamic acid tert-butylester

(3-Isobutyl-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester

EXAMPLE 68 (Method 44) 2-(3,5-Dichloro-phenylsulfanyl)-ethylamine

To a solution of (3,5-dichlorophenylthio)acetonitrile (1.2g) in 3.0 mLof ethylene glycol dimethyl ether is added 0.61 mL of 10M boranedimethyl sulfide complex and the mixture heated at reflux for 0.5 hours.The reaction is cooled in an ice bath and 2.0 mL of water and 2.0 mL ofconcentrated hydrochloric acid is added. This mixture is heated atreflux for 0.5 hr. The clear solution is then cooled and basified withSN sodium hydroxide and extracted with ether. The ether extract is driedover potassium carbonate, filtered and concentrated to give 0.1 g of acolorless oil.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

2-(3-Bromo-phenylsulfanyl)-ethylamine

2-(4-Bromo-phenoxy)-ethylamine

2-(4-Iodo-phenoxy)-ethylamine

2-(3,4-Dichloro-phenoxy)-ethylamine

2-(3-Chloro-phenylsulfanyl)-ethylamine

2-(3,4-Dichloro-phenylsulfanyl)-ethylamine

3-(4-Bromo-phenyl)-propylamine

2-(2-Fluoro-phenoxy)-ethylamine

2-(2-Chloro-phenoxy)-ethylamine

2-(3-Bromo-phenoxy)-ethylamine

2-(3-Fluoro-phenoxy)-ethylamine

2-(3-Iodo-phenoxy)-ethylamine

2-(3,5-Dichloro-phenylsulfanyl)-ethylamine

2-Phenylsulfanyl-ethylamine

1-(2-Chloro-phenyl)-ethylamine

EXAMPLE 69 (Method 45) N-(1-Naphthalen-2-yl-ethyl)-formamide

A mixture of 2-acetylnaphthylene (3.0 g), ammonium formate (11.0 g),formic acid 10 (3.3 mL), and formamide (3.5 mL) is heated at 190° C. for3 hours. The mixture is cooled, poured into water and extracted withether. The ether extract is dried with anhydrous potassium carbonate,filtered and concentrated to give a yellow oil, which is crystallizedfrom toluene-hexanes to give a white solid, 1.97 g.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

N-[1-(4-Fluoro-phenyl)-2-methyl-propyl]-formamide

N-(1-Naphthalen-2-yl-ethyl)-formamide

EXAMPLE 70 (Method 46) 1-(2-Naphthyl)ethylamine

A mixture of N-(1-naphthalen-2-yl-ethyl)-formamide (1.12 g), ethanol (10mL) and 5 N sodium hydroxide (10 mL) is heated at reflux for 1 hour. Thesolution is cooled, poured into water and extracted with ether. Theether solution is dried with anhydrous potassium carbonate, filtered andconcentrated to give the product (0.95 g) as a pale yellow oil.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

1-(3-Trifluoromethyl-phenyl)-ethylamine

1-(4-Fluoro-phenyl)-2-methyl-propylamine

[3-(1-Amino-ethyl)-phenyl]-dimethyl-amine

3-(1-Amino-ethyl)-benzonitrile

EXAMPLE 71 (Method 47) 1-(3-Trifluoromethyl-phenyl)-ethanoneO-methyl-oxime

Methoxylamine hydrochloride (2.33 g) is added to a solution of3′-(trifluoromethyl) acetophenone (1.5 g) in ethanol (20 mL) andpyridine (2 mL). The solution is heated at reflux for 45 minutes. Thereaction mixture is then cooled, concentrated under reduced pressure andpartitioned between water and ethyl acetate. The aqueous layer isextracted with ethyl acetate. The combined organic layers are washedwith saturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure to give the desiredproduct as a colorless oil (1.61 g).

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

3,5-Bis-trifluoromethyl-benzaldehyde oxime

1-(4-Fluoro-phenyl)-propan-1-one O-methyl-oxime

1-(2-Chloro-phenyl)-ethanone O-methyl-oxime

1-(3-Bromo-phenyl)-ethanone O-methyl-oxime

1-(3-Chloro-phenyl)-ethanone O-methyl-oxime

1-o-Tolyl-ethanone O-methyl-oxime

1-(4-Fluoro-phenyl)-pentan-1-one O-methyl-oxime

1-(4-Fluoro-phenyl)-2-phenyl-ethanone O-methyl-oxime

1-o-Tolyl-ethanone O-methyl-oxime

1-m-Tolyl-ethanone O-methyl-oxime

1-(2-Fluoro-phenyl)-ethanone O-methyl-oxime

3-(1-Methoxyimino-ethyl)-benzonitrile

4-(1-Methoxyimino-ethyl)-benzonitrile

1-(4-Methoxy-phenyl)-ethanone O-methyl-oxime

1-(2-Methoxy-phenyl)-ethanone O-methyl-oxime

1-(4-Dimethylamino-phenyl)-ethanone O-methyl-oxime

1-(2-Trifluoromethyl-phenyl)-ethanone O-methyl-oxime

1-(3-Methoxy-phenyl)-ethanone O-methyl-oxime

1-(3-Trifluoromethyl-phenyl)-ethanone O-methyl-oxime

1-(4-Trifluoromethyl-phenyl)-ethanone O-methyl-oxime

1-Furan-2-yl-ethanone O-methyl-oxime

1-Pyridin-4-yl-ethanone O-methyl-oxime

1-(1-Methyl-1H-pyrrol-2-yl)-ethanone O-methyl-oxime

1-Thiophen-3-yl-ethanone O-methyl-oxime

(4-Fluoro-phenyl)-phenyl-methanone O-methyl-oxime

1-(4-methoxyphenyl)ethanone O-methyloxime

1-(3-Chloro-4-methoxy-phenyl)-ethanone O-methyl-oxime

4-(1-Methoxyimino-ethyl)-benzenesulfonamide

4-(1-Methoxyimino-ethyl)-N,N-dimethyl-benzenesulfonamide

1-[4-(Piperidine-1-sulfonyl)-phenyl]-ethanone O-methyl-oxime

4-(1-Methoxyimino-ethyl)-N,N-dipropyl-benzenesulfonamide

2-Fluoro-N-[4-(1-methoxyimino-ethyl)-phenyl]-benzamide

1-(3,5-Bis-trifluoromethyl-phenyl)-ethanone O-methyl-oxime

1-[4-(1H-Imidazol-1-yl)phenyl]-1-ethanone, O-methyloxime

1-[4-(Trifluoromethyl)phenyl]-1-ethanone, O-methyloxime

1-[1,1′-Biphenyl]-4-yl-1-ethanone, O-methyloxime

1-(4-Methylphenyl)-1-ethanone, O-methyloxime

1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone O-methyloxime

1-[3,5-bis(trifluoromethyl)phenyl]ethanone O-benzyloxime

1-[4-chloro-3-(trifluoromethyl)phenyl]ethanone O-methyloxime

1-[3-fluoro-5-(trifluoromethyl)phenyl]ethanone O-methyloxime

1-[2-fluoro-4-(trifluoromethyl)phenyl]ethanone O-methyloxime

1-[2-fluoro-5-(trifluoromethyl)phenyl]ethanone O-methyloxime

1-(2,4-dichlorophenyl)ethanone O-methyloxime

1-(2,4-dimethylphenyl)ethanone O-methyloxime

1-[2,4-bis(trifluoromethyl)phenyl]ethanone O-methyloxime

1-(3-bromophenyl)ethanone O-methyloxime

1-(3-methylphenyl)ethanone O-methyloxime

1-[4-(4-morpholinyl)phenyl]ethanone O-methyloxime

1-(2-chloro-4-fluorophenyl)ethanone O-methyloxime

1-(4-bromo-2-fluorophenyl)ethanone O-methyloxime

1-(3,4-difluorophenyl)ethanone O-methyloxime

1-[3-(trifluoromethyl)phenyl]ethanone O-methyloxime

1-[2-(trifluoromethyl)phenyl]ethanone O-methyl oxime

1-(2,4-difluorophenyl)ethanone O-methyloxime

1-[3-fluoro-4-(trifluoromethyl)phenyl]ethanone O-methyloxime

1-(3,4-dichlorophenyl)ethanone O-methyloxime

1-[4-fluoro-2-(trifluoromethyl)phenyl]ethanone O-methyloxime

1-(3-chloro-4-fluorophenyl)ethanone O-methyloxime

1-(4-chloro-3-fluorophenyl)ethanone O-methyloxime

1-(2,5-difluorophenyl)ethanone O-methyloxime

1-(2-bromo-4-fluorophenyl)ethanone O-methyloxime

1-(3,4-dibromophenyl)ethanone O-methyloxime

1-(2-bromophenyl)ethanone O-methyloxime

EXAMPLE 72 (Method 48) 1-(2-Trifluoromethyl-phenyl)-ethylamine

Sodium borohydride (1.17 g) is added slowly to a flask containingzirconium tetrachloride (1.8 g) in tetrahydrofuran (27 mL). A solutionof 1-(2-trifluoromethyl-phenyl)-ethanone O-methyl-oxime (1.34 g) intetrahydrofuran (7.7 mL) is added and the resulting solution is stirredat 25° C. for 12 hours. The reaction mixture is then cooled to 0° C. andwater (16 mL) is slowly added. Excess ammonium hydroxide is added andthe solution is extracted twice with ethyl acetate. The organic portionis washed twice with 1N hydrochloric acid. The aqueous (acid) layer isbasified with sodium hydroxide and extracted twice with ethyl acetate.The organic layer is then washed with saturated aqueous sodium chlorideand dried over anhydrous magnesium sulfate. The solvent is removed underreduced pressure to provide the desired product as a yellow oil (0.20g).

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

1-(3-Methoxy-phenyl)-ethylamine

1-(4-Fluoro-phenyl)-propylamine

1-Naphthalen-2-yl-ethylamine

4-(1 -Amino-ethyl)-benzonitrile

1-(4-Trifluoromethyl-phenyl)-ethylamine

1-(4-Methoxy-phenyl)-ethylamine

1-Prop-2-ynyl-pyrrolidine

1-(2-Methoxy-phenyl)-ethylamine

1-m-Tolyl-ethylamine

1-(2-Bromo-phenyl)-ethylamine

1-o-Tolyl-ethylamine

C-(4-Fluoro-phenyl)-C-phenyl-methylamine

1-(4-Fluoro-phenyl)-pentylamine

1-(4-Fluoro-phenyl)-2-phenyl-ethylamine

1 -(2-Trifluoromethyl-phenyl)-ethylamine

1-(3-Bromo-phenyl)-ethylamine

1-(3-Chloro-phenyl)-ethylamine

[4-(1-Amino-ethyl)-phenyl]-dimethyl-amine

1-(1-Methyl-1H-pyrrol-2-yl)-ethylamine

1-[3,5-bis(trifluoromethyl)phenyl]propylamine

1-[3,5-bis(trifluoromethyl)phenyl]-1-butanamine or1-[3,5-bis(trifluoromethyl)phenyl]butylamine

1-[3,5-bis(trifluoromethyl)phenyl]-1-pentanamine

1-(4-methylphenyl)ethanamine

1-[4-(trifluoromethyl)phenyl]ethylamine

1-(3-methylphenyl)ethanamine

1-(3,4-dichlorophenyl)ethanamine

1-(2-Bromo-phenyl)-ethylamine

1-(2-Trifluoromethyl-phenyl)-ethylamine

1-(3-Bromo-phenyl)-ethylamine

1-(3-Chloro-4-methoxy-phenyl)-ethylamine

4-(1-Amino-ethyl)-N,N-dimethyl-benzenesulfonamide

1-[4-(Piperidine-1-sulfonyl)-phenyl]-ethylamine

1-Quinolin-6-yl-ethylamine

1-(3,5-Bis-trifluoromethyl-phenyl)-ethylamine

4-[(1S)-1-aminoethyl]benzonitrile

(S)-alpha-Methyl-3,5-bis(trifluoromethyl)-benzenemethanamine(S)-alpha-Methyl-3,5-bis(trifluoromethyl)-benzenemethanamine

1-Biphenyl-4-yl-ethylamine

1-(4-Fluoro-phenyl)-ethylamine

1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanamine

1-[4-chloro-3-(trifluoromethyl)phenyl]ethanamine

N-{4-[(1R)-1-aminoethyl]pheny}-1,2,3-thiadiazole-4-carboxamide

N-{4-[(1S)-1-aminoethyl]phenyl}-1,2,3-thiadiazole-4-carboxamide

1-[3-fluoro-5-(trifluoromethyl)phenyl]ethylamine

1-[2-fluoro-4-(trifluoromethyl)phenyl]ethylamine

1-[2-fluoro-5-(trifluoromethyl)phenyl]ethylamine

1-(2,4-dichlorophenyl)ethylamine

1-(2,4-dimethylphenyl)ethylamine

1-[2,4-bis(trifluoromethyl)phenyl]ethylamine

1-(2-chloro-4-fluorophenyl)ethylamine

1-(3,4-difluorophenyl)ethylamine

1-(4-bromo-2-fluorophenyl)ethylamine

1-(3-fluorophenyl)ethylamine

1-(2,4-difluorophenyl)ethylamine

1-[3-fluoro-4-(trifluoromethyl)phenyl]ethylamine

1-[4-fluoro-2-(trifluoromethyl)phenyl]ethylamine

1-(3-chloro-4-fluorophenyl)ethylamine

1-(4-chloro-3-fluorophenyl)ethylamine

1-(3 ,4-dibromophenyl)ethylamine

1-(2-bromo-4-fluorophenyl)ethanamine1-(2-bromo-4-fluorophenyl)ethylamine

EXAMPLE 73 (Method 49) (2-Fluoro-5-trifluoromethyl-phenoxy)-acetonitrile

A solution of 2-fluoro-5-trifluoromethylphenol (25 g) in reagent gradeacetone (0.55 L) is treated with solid potassium carbonate (7.7 g)followed by the rapid addition of neat bromoacetonitrile (10 mL). Theheterogenous mixture is stirred vigorously for approximately 20 hourswhereupon it is poured into water and extracted into diethyl ether. Thecombined ether extracts are washed with saturated sodium chloride anddried over anhydrous potassium carbonate. Filtration and concen-trationunder reduced pressure gives a pale orange solid which is thenchromatographed on silica gel, eluting with dichloromethane, to give thedesired product as white solid (28.3 g).

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

(3-Bromo-phenylsulfanyl)-acetonitrile

(3-Chloro-phenylsulfanyl)-acetonitrile

(4-Iodo-phenoxy)-acetonitrile

(3-Trifluoromethyl-phenylsulfanyl)-acetonitrile

(3,5-Dichloro-phenylsulfanyl)-acetonitrile

(3 ,4-Dichloro-phenylsulfanyl)-acetonitrile

(3,4-Dichloro-phenoxy)-acetonitrile

(2-Fluoro-phenoxy)-acetonitrile

(3-Fluoro-phenoxy)-acetonitrile

(2-Chloro-phenoxy)-acetonitrile

(3-Bromo-phenoxy)-acetonitrile

(2-Fluoro-5-trifluoromethyl-phenoxy)-acetonitrile

(3-Iodo-phenoxy)-acetonitrile

(4-Bromo-phenoxy)-acetonitrile

EXAMPLE 74 (Method 50) 3-Fluoro-5-trifluoromethylphenethylamine Tosylate

A solution of 2.5 g of 3-fluoro-5-trifluoromethylphenylacetonitrile and2.34 g (12.3 mmol) of p-toluenesulfonic acid in 75 ml of ethylene glycolmonomethyl ether is hydrogenated for 3 hours at room temperature at 40psi, using 200 mg 10% palladium on carbon catalyst. The catalyst isfiltered off and the solvent evaporated to half the volume. Uponstanding, the p-toluenesulfonic acid salt of the desired3-fluoro-5-trifluoromethylphenethylamine crystallizes. The whitecrystals, 4.26g (91%) are collected by filtration.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

2-(3,5-Difluoro-phenyl)-ethylamine

2-(4-Trifluoromethyl-phenyl)-ethylamine

2-(3,4-Difluoro-phenyl)-ethylamine

2- (2-Fluoro-phenyl)-ethylamine

2-(3-Fluoro-5-trifluoromethyl-phenyl)-ethylamine

2-(2-Fluoro-3-trifluoromethyl-phenyl)-ethylamine

2-(2,4-Bis-trifluoromethyl-phenyl)-ethylamine

2-(4-Fluoro-3-trifluoromethyl-phenyl)-ethylamine

EXAMPLE 75 (Method 51)(4-Aminomethyl-2-trifluoromethyl-phenyl)-dimethyl-amine

A solution of 4-dimethylamino-3-trifluoromethylbenzonitrile (0.35 g) intetrahydrofuran (2 mL) is slowly added to a suspension of lithiumaluminum hydride (0.1 g) in tetrahydrofuran (2 mL) at 0° C. and stirredunder an atmosphere of argon for 2 hours. While at 0° C. water (0.1 mL)is slowly added followed by 5% sodium hydroxide (0.1 mL) and water (0.3mL). The resulting gray solid is filtered and washed withtetrahydrofuran. The filtrates are collected and concentrated underreduced pressure and the resulting oil is chromatographed over silicagel (15% methanol in methylene chloride is used as the eluant) toprovide the desired product as a pale orange oil (0.164 g).

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

4-Piperidin-1-yl-3-trifluoromethyl-benzylamine

(4-Aminomethyl-2-trifluoromethyl-phenyl)-dimethyl-amine

4-(4-Methyl-piperazin-1-yl)-3-trifluoromethyl-benzylamine

(3-Aminomethyl-5-trifluoromethyl-phenyl)-dimethyl-amine

[3-(2-Amino-ethyl)-5-trifluoromethyl-phenyl]-dimethyl-amine

[4-(2-Amino-ethyl)-2-methyl-phenyl]-dimethyl-amine

EXAMPLE 76 (Method 52) 3-Dimethylamino-5-trifluoromethyl-benzaldehyde

Diisobutylaluminum hydride (10 mL of a IM solution in methylenechloride) is added dropwise to a solution of3-dimethylamino-5-trifluoromethylbenzonitrile (1.06 g) in methylenechloride (25 mL) at 0° C. and the mixture stirred for 2 hours. Whilestill at 0° C. a saturated aqueous solution of sodium potassium tartrate(8 mL) is slowly added and the solution is stirred for 1.5 hours. Thereaction mixture is then extracted with ethyl acetate, dried overanhydrous magnesium sulfate and concentrated under reduced pressure toprovide the desired product as a yellow solid (0.97 g).

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

3-Dimethylamino-5-trifluoromethyl-benzaldehyde

4-Dimethylamino-3-methyl-benzaldehyde

EXAMPLE 77 (Method 53)Dimethyl-[3-(2-nitro-vinyl)-5-trifluoromethyl-phenyl]-amine

Nitromethane (0.473 g) is added to a solution of3-dimethylamino-5-trifluoromethyl-benzaldehyde (0.885 g) and ammoniumacetate (0.339 g) in acetic acid (3.4 mL) and the solution is heated at110° C. for 6 hours. The reaction mixture is cooled to 0° C. and a solidforms which is filtered and washed with 1:1 water-acetic acid. Thissolid is recrystallized from ethanol to provide the desired product as ared solid (0.39 g).

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

Dimethyl-[3-(2-nitro-vinyl)-5-trifluoromethyl-phenyl]-amine

Dimethyl-[ 2-methyl-4-(2-nitro-vinyl)-phenyl]-amine

EXAMPLE 78 (Method 54) 3-(4-Bromo-phenyl)-propionitrile

Diethylazodicarboxylate (5.2 g) is added dropwise to a solution of4-bromo-phenethylalcohol (2.01 g), and triphenylphosphine (7.9 g) indiethyl ether (16 mL) at 0° C. The reaction mixture is stirred for 10minutes and a solution of acetone cyanohydrin (2.6 g) in diethyl ether(10 mL) is added. The clear orange solution is stirred for 5 minutes at0° C. and then at 25° C. for 12 hours. The reaction mixture is thenfiltered, and washed with diethyl ether. The filtrate is concentratedunder reduced pressure and chromatographed over silica gel (10% ethylacetate-hexanes is 15 used as the eluant) to provide the desired productas a pale yellow oil (2.04 g).

EXAMPLE 79 (Method 55) 3-Dimethylamino-2-isocyano-acrylic acid ethylester

To a solution of ethyl isocyanoacetate (5.0 g) in ethanol (100 mL) isadded N,N-dimethyl-formamide dimethyl acetal (6.5 g) dropwise withstirring over 10 minutes.

The reaction is stirred for 24 hours and the ethanol is evaporated. Theresulting oil is passed through magnesium silicate using 50% ethylacetate-hexanes as the eluant. The solvents are removed and theresulting oil is crystallized from ethyl acetate-hexanes to yield lightyellow needles, 3.0 g.

EXAMPLE 80 (Method 56) 4-Carboethoxythiazole

A solution of 3-dimethylamino-2-isocyano-acrylic acid ethyl ester (1.0g) and triethylamine (3.0 g) in tetrahydrofuran (30 mL) is treated withgaseous hydrogen sulfide until all starting material is consumed. Themixture is concentrated to an oil and purified by column chromatographyusing silica and 25% ethyl acetate-hexanes as the eluant. The purifiedmaterial (0.61 g) is isolated as an oil.

EXAMPLE 81 (Method 34)N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-ureido]-phenyl}-2-fluoro-benzamide

A suspension of N-(4-amino-phenyl)-2-fluoro-benzamide (0.43 g) inacetonitrile (4 mL) is treated with5-chloro-2,4-dimethoxyphenylisocyanate (0.40 g). The mixture becomes asolution and is allowed to stand for 12 hours. A white solid forms andis collected by filtration (0.79 g). [M+H] 444.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

EX NO. M + H COMPOUND NAME 81 445N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-ureido]-phenyl}-2-fluoro-benzamide 82 441N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-ureido]-phenyl}-2-methyl-benzamide 83 435 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3- (5-chloro-2,4-dimethoxy-phenyl)-ureido]-phenyl}- amide 84 443[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-chloro-3-trifluoromethyl-phenyl)-ureido]-phenyl} amide 85 453N-{4[3-(4-Chloro-3-trifluoromethyl-phenyl)-ureido]-phenyl}-2-fluoro-benzamide 86 409 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,5- dichloro-phenyl)-ureido]-phenyl}-amide 87 486N-{4-[3-(3,5-Bis-trifluoromethyl-phenyl)-ureido]-phenyl}-2-fluoro-benzamide 88 458 Furan-2-carboxylic acid{4-[3-(3,5-bis-trifluoromethyl- phenyl)-ureido]-phenyl}-amide 89 476[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-phenyl)-ureido]-phenyl}-amide 90 423[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,4-dichloro-benzyl)-ureido]-phenyl}-amide

EXAMPLE 91 (Method 31)N-(5-{[({(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}-2-pyridinyl)-1,3-thiazole-4-carboxamide

A mixture of N-(5-isothiocyanato-2-pyridinyl)-1,3-thiazole-4-carboxamide(0.36 g) and(S)-alpha-methyl-3,5-bis(trifluoromethyl)-benzenemethanamine (0.36 g) isheated with acetonitrile (10 mL) until all solids are dissolved. Thesolution is allowed to stand for 12 hours. A white solid forms and iscollected by filtration (0.40 g). [M+H] 520.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

EX. NO. M + H COMPOUND NAME 92 506[3-Chloro-5-(3-{4-[([1,2,3]thiadiazole-4-carbonyl)-amino]-phenyl}-thioureido)-phenyl]-carbamicacid tert-butyl ester 93 4091-(5-Chloro-2,4-dimethoxy-phenyl)-3-(4-morpholin-4-yl-phenyl)-thiourea94 3701-(5-Chloro-2,4-dimethoxy-phenyl)-3-(4-methylsulfanyl-phenyl)-thiourea95 338 1-(5-Chloro-2,4-dimethoxy-phenyl)-3-p-tolyl-thiourea 96 414{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenylsulfanyl}-aceticacid 97 3841-(5-Chloro-2,4-dimethoxy-phenyl)-3-[4-(2-hydroxy-ethoxy)-phenyl]-thiourea98 340 1-(5-Chloro-2,4-dimethoxy-phenyl)-3-(4-hydroxy-phenyl)-thiourea99 395N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-N-methyl-acetamide100 381N-{(3-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide101 411{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-carbamic acidethyl ester 102 3191-(2,4-Dimethoxy-phenyl)-3-(4-methoxy-phenyl)-thiourea 103 346N-{4-[3-(2,4-Dimethoxy-phenyl)-thioureido]-pbenyl-acetamide 104 316N-{4-[3-(4-Methoxy-phenyl)-thioureido]-phenyl}-acetamide 105 316N-{4-[3-(2-Methoxy-phenyl)-thioureido]-phenyl}-acetamide 106 351N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide 107351 N-{4-[3-(5-Chloro-2-methoxy-phenyl)-thioureido]-phenyl}-acetamide108 371N-{4-[3-(3,5-Dichloro-4-hydroxy-phenyl)-thioureido]-phenyl}-acetamide109 385N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide110 381N-{4-[3-(4-Chloro-2,5-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide111 389N-{4-[3-(2-Chloro-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-acetamide112 389N-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-acetamide113 422 Benzoic acid4-[3-(4-acetylamino-phenyl)-thioureido]-3-hydroxy-phenylester 114 457N-{4-[3-(5-Chloro-2,4-dimethoxy-pbenyl)-thioureido]-phenyl}-2-methyl-benzamide115 501 Acetic acid2-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl-carbamoyl}-phenylester 116 461N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-4-fluoro-benzamide117 461N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-fluoro-benzamide118 461N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide119 473N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-methoxy-benzamide120 473N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-methoxy-benzamide121 473N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-4-methoxy-benzamide122 443N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-benzamide123 417N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-mehtanesulfonamide124 331 N-{4-[3-(3-Nitro-phenyl)-thioureido]-phenyl}-acetamide 125 3391-(3-Chloro-4-methoxy-phenyl)-3-(3-nitro-phenyl)-thiourea 126 337N-{4-[3-(5-Chloro-2-hydroxy-phenyl)-thioureido]-phenyl}-acetamide 127439 {4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-carbamicacid tert-butyl ester 128 351N-{4-[3-(3-Chloro-4-hydroxy-5-methyl-phenyl)-thioureido]-phenyl}-acetamide129 385N-{4-[3-(3,5-Dichloro-4-hydroxy-2-methyl-phenyl)-thioureido]-phenyl}-acetamide130 318 N-{4-[3-(2,4-Dihydroxy-phenyl)-thioureido]-phenyl}-acetamide 131414N-{4-[3-(2,4-Dimethoxy-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-acetamide132 332N-{4-[3-(2-Hydroxy-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide 133465N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-4-fluoro-benzamide134 5003-Acetylamino-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-benzamide135 488N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-nitro-benzamide136 486N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-dimethylamino-Benzamide137 536N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-methane-sulfony-amino-benzamide138 511N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-trifluoro-methyl-benzamide139 459N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-hydroxy-benzamide140 479N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2,6-difluoro-benzamide141 4772-Chloro-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-benzamide142 5222-Bromo-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-benzamide143 488N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-nitro-benzamide144 445 Pyrazine-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 145 4635-Methyl-thiophene-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 146 494Quinoline-8-carboxlic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 147 4461-Methyl-1H-pyrrole-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 148 3691-(5-Chloro-2,4-dimethoxy-phenyl)-3-(2-nitro-phenyl)-thiourea 149 3691-(5-Chloro-2,4-dimethoxy-phenyl)-3-(4-nitro-phenyl)-thiourea 150 425N-{4-[3-(5-Bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide 151376 N-{4-[3-(3,4,5-Trimethoxy-phenyl)-thioureido]-phenyl}-acetamide 152399N-{4-[3-(3,5-Dichloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-acetamide153 499 Benzo[b]thiophene-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 154 483Benzofuran-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 155 444N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-isonicotinamide156 493 Naphthalene-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 157 493Naphthalene-1-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl}-amide 158 494Isoquinoline-1-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 159 494Quinoline-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 160 444N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-nicotinamide161 478 5-Nitro-furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amidecarbamicacid phenyl ester 162 459{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}- 163 4675-Chloro-furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 164 439{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-carbamic acidisobutyl ester 165 397{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-carbamic acidmethyl ester 166 433 Furan-3-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 167 4473-Methyl-furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 168 5125-Bromo-furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 169 5124-Bromo-furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 170 433Furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 171 467{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-carbamic acidhexyl ester 172 494 Isoquinoline-4-carhoxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 173 451[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 174 4341H-[1,2,3]Triazole-4-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 175 5283-Bromo-thiophene-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 176 399N-{4-[3-(3,5-Dichloro-4-ethoxy-phenyl)-thioureido]-phenyl}-acetamide 177427 N-{4-[3-(4-Butoxy-3,5-dichloro-phenyl)-thioureido]-phenyl}-acetamide178 461N-{4-[3-(4-Benzyloxy-3,5-dichloro-phenyl)-thioureido]-phenyl}-acetamide179 381N-{4-[3-(3-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide180 530(3-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenylcarbamoyl}-phenyl)-carbamicacid ethyl ester 181 4582-Amino-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-benzamide182 519 Biphenyl-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 183 4691-(5-Chloro-2,4-dimethoxy-phenyl)-3-[4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-phenyl]-thiourea184 487N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-phthalamicacid 185 473N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-hydroxy-methyl-benzamide186 479N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2,3-difluoro-benzamide187 479N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2,5-difluoro-benzamide188 479N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2,4-difluoro-benzamide189 5002-Acetylamino-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-benzamide190 4411-(5-Chloro-2,4-dimethoxy-phenyl)-3-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-thiourea191 536N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-methane-sulfonylamino-benzamide192 497N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl-2,3,4-trifluoro-benzamide193 533N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2,3,4,5,6-pentafluoro-benzamide194 489N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-methyl-sulfanyl-benzamide195 431 5-Methyl-furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-ureido]-phenyl}-amide 196 4675-Difluoromethyl-furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-ureido]-phenyl}-amide 197 472N-{4-[3-(5-Iodo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide 198364N-{4-[3-(5-Fluoro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide199 365N-{4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-acetamide200 459 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 201455 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,5-dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-amide 202 392N-{4-[3-(3-Chloro-4-diethylamino-phenyl)-thioureido]-phenyl}-acetamide203 432N-(4-{3-[3-Chloro-4-(cyclohexyl-methyl-amino)-phenyl]thioureido}-phenyl)-acetamide204 506 1-Hydroxy-naphthalene-2-carboxylic acid{4-[3-(4-acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-amide 205 406N-{4-[3-(3-Chloro-4-morpholin-4-yl-phenyl)-thioureido]-phenyl}-acetamide206 4431-(5-Chloro-2,4-dimethoxy-phenyl)-3-(3-chloro-4-morpholin-4-yl-phenyl)-thiourea207 3721-(5-Chloro-2,4-dimethoxy-phenyl)-3-(5-chloro-2-methyl-phenyl)-thiourea208 501N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-isophthalamicacid methyl ester 209 487N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-isophthalamicacid 210 5493-Benzyloxy-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-benzamide 211 434N-(4-{3-[5-Chloro-2-methoxy-4-(4-nitrilo-butoxy)-phenyl]-thioureido}-phenyl)-acetamide212 406N-(4-{3-[5-Chloro-2-methoxy-4-(2-nitrilo-ethoxy)-phenyl]-thioureido}-phenyl)-acetamide213 406N-(4-{3-[5-Chloro-4-methoxy-2-(2-nitrilo-ethoxy)-phenyl]-thioureido}-phenyl)-acetamide214 411N-(4-{3-[5-Chloro-2-(2-hydroxy-ethoxy)-4-methoxy-phenyl]-thioureido}-phenyl)-acetamide215 411N-(4-{3-[5-Chloro-4-(2-hydroxy-ethoxy)-2-methoxy-phenyl]-thioureido}-phenyl)-acetamide216 481{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-5-methoxy-phenoxy}-aceticacid tert-butyl ester 217 439{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-5-methoxy-phenoxy}-aceticacid methyl ester 218 481{2-[3-(4-Acetylamino-phenyl)-thioureido]-4-chloro-5-methoxy-phenoxy}-aceticacid tert-butyl ester 219 5153-Butoxy-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl]-benzamide220 505 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-methane-sulfinyl-benzamide 221 545(3-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenylcarbamoyl}-phenoxy)-aceticacid ethyl ester 222 517(3-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenylcarbamoyl}-phenoxy)-aceticacid 223 367N-{4-[3-(5-Chloro-4-hydroxy-2-methoxy-phenyl)-thioureido]-phenyl}-acetamide224 444 Pyridine-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 225 494Quinoline-4-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 226 436N-{4-[3-(5-Chloro-4-methoxy-2-morpholin-4-yl-phenyl)-thioureido]-phenyl}-acetamide227 394N-{4-[3-(5-Chloro-2-dimethylamino-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide228 420N-{4-[3-(5-Chloro-4-methoxy-2-pyrrolidin-1-yl-phenyl)-thioureido]-phenyl}-acetamide229 434N-{4-[3-(5-Chloro-4-methoxy-2-piperidin-1-yl-phenyl)-thioureido]-phenyl}-acetamide230 405 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-chloro-4-methyl-phenyl)-thioureido]-phenyl}-amide 231 415N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide232 427N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]-phenyl}-3-methoxy-benzamide233 387 Furan-2-carboxylic acid{4-[3-(3-chloro-4-methyl-phenyl-thioureido]-phenyl}-amide 234 411N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]-phenyl}-2-methyl-benzamide235 433N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]-phenyl}-2,6-difluoro-benzamide236 398 Pyridine-2-carboxylic acid{4-[3-(3-chloro-4-methyl-phenyl)-thioureido]-phenyl}-amide 237 502[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[3-chloro-4-(cyclohexyl-methyl-amino)-phenyl]-thioureido}-phenyl)-amide238 512N-(4-{3-[3-Chloro-4-(cyclohexyl-methyl-amino)-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide239 404N-{4-[3-(3-Chloro-4-piperidin-1-yl-phenyl)-thioureido]-phenyl}-acetamide240 364N-{4-[3-(3-Chloro-4-dimethylamino-phenyl)-thioureido]-phenyl}-acetamide241 426N-{4-[3-(4-Benzylamino-3-chloro-phenyl)-thioureido]-phenyl}-acetamide242 390N-{4-[3-(3-Chloro-4-pyrrolidin-1-yl-phenyl)-thioureido]-phenyl}-acetamide243 419N-(4-{3-[3-Chloro-4-(4-methyl-piperazin-1-yl)-phenyl]-thioureido}-phenyl)-acetamide244 469N-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide245 422N-{4-[3-(2-Benzylamino-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide246 484 Furan-2-carboxylic acid(4-{3-[3-chloro-4-(cyclohexyl-methyl-amino)-phenyl]-thioureido}-phenyl)-amide247 508N-(4-{3-[3-Chloro-4-(cyclohexyl-methyl-amino)-phenyl]-thioureido}-phenyl)-2-methyl-benzamide248 530N-(4-{3-[3-Chloro-4-(cyclohexyl-methyl-amino)-phenyl]-thioureido}-phenyl)-2,6-difluoro-benzamide249 495 Pyridine-2-carboxylic acid(4-{3-[3-chloro-4-(cyclohexyl-methyl-amino)-phenyl]-thioureido}-phenyl)-amide250 524N-(4-{3-[3-Chloro-4-(cyclohexyl-methyl-amino)-phenyl]-thioureido}-phenyl)-3-methoxy-benzamide251 376N-(4-{3-[3-Chloro-4-(2-nitrilo-ethoxy)-phenyl]-thioureido}-phenyl)-acetamide252 393N-{4-[3-(4-sec-Butoxy-3-chloro-phenyl)-thioureido]-phenyl}-acetamide 253501 Acetic acid3-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl-carbamoyl}-phenylester 254 459N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-hydroxy-benzamide255 487 Benzol[1,3]dioxole-4-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 256 527N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-trifluoro-methoxy-benzamide257 530N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-(2-dimethylamino-ethoxy)-benzamide258 572N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-(2-morpholin-4-yl-ethoxy)-benzamide259 406N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-cyano-phenyl}-acetamide260 521N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2,5-dimethoxy-phenyl}-2-fluoro-benzamide261 441N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2,5-dimethoxy-phenyl}-acetamide262 5272-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenoxy}-5-chloro-benzenesulfonicacid 263 5622-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenoxy}-4,5-dichloro-benzenesulfonicacid 264 527 4-Phenyl-[1,2,3]thiadiazole-5-carboxylicacid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 265381N-(4-{3-[3-Chloro-4-(2-hydroxy-ethoxy)-phenyl]-thioureido}-phenyl)-acetamide266 393 N-{4-[3-(4-Butoxy-3-chloro-phenyl)-thioureido]-phenyl}-acetamide267 446N-(4-{3-[3-Chloro-4-(cyclohexyl-ethyl-amino)-phenyl]-thioureido}-phenyl)-acetamide268 365 N-{4-[3-(3-Chloro-4-ethoxy-phenyl)-thioureido]-phenyl}-acetamide269 427N-{4-[3-(4-Benzyloxy-3-chloro-phenyl)-thioureido]-phenyl}-acetamide 270317 {4-[(3-Methyl-furan-2-carbonyl)-amino]-phenyl}-carbamicacidtert-butyl ester 271 456N-{4-[3-(2-Benzylamino-5-chloro-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide272 420N-{4-[3-(3-Chloro-4-dipropylamino-phenyl)-thioreido]-phenyl}-acetamide273 458N-(4-{3-[4-(Allyl-cyclohexyl-amino)-3-chloro-phenyl]-thioureido}-phenyl)-acetamide274 411N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methoxy-phenyl}-acetamide275 415N-{2-Chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide276 493 Furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2,5-dimethoxy-phenyl}-amide277 486N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-cyano-phenyl}-2-fluoro-benzamide278 495N-{2-Chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide279 465 5-Methyl-[1,2,3]thiadiazole-4-carboxylicacid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 280517 5-Furan-3-yl-[1,2,3]thiadiazole-4-carboxylicacid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}amide 281527 5-Phenyl-[1,2,3]thiadiazole-4-carboxylicacid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 282458N-(4-{3-[3-Chloro-4-(octahydro-quinolin-1-yl)-phenyl]-thioureido}-phenyl)-acetamide283 458N-[5-[[[(5-Chloro-2,4-dimethoxyphenyl)amino]thioxomethyl]amino]-2-pyridinyl]-2-methylbenzamide284 434 Furan-2-carboxylic acid{5-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-2-yl}-amide285 425N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methoxy-5-methyl-phenyl}-acetamide286 505N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methoxy-5-methyl-phenyl}-2-fluoro-benzamide287 477 Furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methoxy-5-methyl-phenyl}-amide288 517 4-Furan-3-yl-[1,2,3]thiadiazole-5-carboxylicacid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 289462N-{5-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-2-yl}-2-fluoro-benzamide290 384N-{4-[3-(4-Methoxy-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-acetamide291 394N-[4-(3-{3-Chloro-4-[(2-hydroxy-ethyl)-methyl-amino]-phenyl}-thioureido)-phenyl]-acetamide292 485N-{2-Benzoyl-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide293 565N-{2-Benzoyl-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide294 537 Furan-2-carboxylic acid{2-benzoyl-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide295 475N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methyl-phenyl}-2-fluoro-benzamide296 447 Furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methyl-phenyl}-amide297 395N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methyl-phenyl}-acetamide298 435N-[4-(3-{3-Chloro-4-[(3-dimethylamino-propyl)-methyl-amino]-phenyl}-thioureido)-phenyl]-acetamide299 418N-{4-[3-(3-Chloro-4-cyclohexylamino-phenyl)-thioureido]-phenyl}-acetamide300 421N-[4-(3-{3-Chloro-4-[(2-dimethylamino-ethyl)-methyl-amino]-phenyl}-thioureido)-phenyl]-acetamide301 5805-[[[(5-Chloro-2,4-dimethoxyphenyl)amino]thioxomethyl]amino]-2-[(2-fluorobenzoyl)amino]-N-phenyl-benzamide302 552 Furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-phenylcarbamoyl-phenyl}-amide303 491N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methoxy-phenyl}-2-fluoro-benzamide304 463 Furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methoxy-phenyl}-amide305 449N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-trifluoromethyl-phenyl}-acetamide306 458 Furan-2-carboxylicacid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-cyano-phenyl}-amide307 467 Furan-2-carboxylic acid{2-chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide308 501 Furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-trifluoromethyl-phenyl}-amide309 395N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methyl-phenyl}-acetamide310 475N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methyl-phenyl}-2-fluoro-benzamide311 447 Furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methyl-phenyl}-amide312 378N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-acetamide313 408{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-carbamic acidethyl ester 314 382N-{5-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-2-yl}-acetamide315 509N-(4-{3-[4-(1-Benzyl-piperidin-4-ylamino)-3-chloro-phenyl]-thioureido}-phenyl)-acetamide316 407N-(4-{3-[3-Chloro-4-(2-dimethylamino-ethylamino)-phenyl]-thioureido}-phenyl)-acetamide317 408N-[4-(3-{3-Chloro-4-[(2-methoxy-ethyl)-methyl-amino]-phenyl}-thioureido)-phenyl]-acetamide318 421N-(4-{3-[3-Chloro-4-(3-dimethylamino-propylamino)-phenyl]-thioureido}-phenyl)-acetamide319 495N-(4-{3-[4-(1-Benzyl-pyrrolidin-3-ylamino)-3-chloro-phenyl]-thioureido}-phenyl)-acetamide320 483 Furan-2-carboxylic acid{5-chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-hydroxy-phenyl}-amide321 431N-{5-Chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-hydroxy-phenyl}-acetamide322 511(5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(2-chloro-4-imidazol-1-yl-phenyl)-methanone323 451 [1,2,3]Thiadiazole-5-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 324 483Furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido)-naphthalen-1-yl}-amide325 511N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-naphthalen-1-yl}-2-fluoro-benzamide326 429N-{5-Chloro-4-[3-(5-chloro-2,4-dimetboxy-phenyl)-thioureido]-2-methyl-phenyl}-acetamide327 509N-{5-Chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methyl-phenyl}-2-fluoro-benzamide328 481 Furan-2-carboxylic acid{5-chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methyl-phenyl}-amide329 431N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-naphthalen-1-yl}-acetamide330 416 Furan-2-carboxylic acid{4-[3-(3-chloro-4-dimethylamino-phenyl)-thioureido]-phenyl}-amide 331561 Furan-2-carboxylic acid[4-(3-{4-[(1-benzyl-pyrrolidin-3-yl)-methyl-amino]-3-chloro-phenyl}-thioureido)-phenyl]-amide332 513N-[4-(3-{3-Chloro-4-[methyl-(1-methyl-pyrrolidin-3-yl)-amino]-phenyl}-thioureido)-phenyl)-2-fluoro-benzamide333 463N-{4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-2,6-difluoro-benzamide334 420N-(4-{3-[3-Chloro-4-(1-methyl-pyrrolidin-3-yloxy)-phenyl]-thioureido}-phenyl)-acetamide335 434N-(4-{3-[3-Chloro-4-(1--methyl-piperidin-4-yloxy)-phenyl)-thioureido}-phenyl)-acetamide336 422N-(4-{3-[3-Chloro-4-(3-dimethylamino-propoxy)-phenyl]-thioureido}-phenyl)-acetamide337 4252-Acetylamino-5-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-benzoicacid 338 5055-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-(2-fluoro-benzoylamino)-benzoicacid 339 4775-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-[(furan-2-carbonyl)-amino]-benzoicacid 340 545N-[4-(3-{3-Chloro-4-[methyl-(1-methyl-piperidin-4-yl)-amino]-phenyl}-thioureido)-phenyl]-2,6-difluoro-benzamide341 503 [1,2,3]Thiadiazole-4-carboxylicacid[4-(3-{3-chloro-4-[methyl-(1-methyl-pyrrolidin-3-yl)-amino]-phenyl}-thioureido)-phenyl]-amide342 443N-{4-[3-(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]-phenyl}-2-methyl-benzamide343 408N-(4-(3-[3-Chloro-4-(2-dimethylamino-ethoxy)-phenyl]-thioureido}-phenyl)-acetamide344 499 Furan-2-carboxylic acid[4-(3-{3-chloro-4-[methyl-(1-methyl-piperidin-4-yl)-amino]-phenyl}-thioureido)-phenyl]-amide 345 419N-{4-[3-(3-Chloro-4-cyclohexyloxy-phenyl)-thioureido]-phenyl}-acetamide346 440N-{4-[3-(3-Chloro-4-dimethylamino-phenyl)-thioureido]-phenyl}-2-methyl-benzamide347 493N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methyl-phenyl}-2,6-difluoro-benzamide348 462N-{4-[3-(3-Chloro-4-dimethylamino-phenyl)-thioureido]-phenyl}-2,6-difluoro-benzamide349 531N-[4-(3-{3-Chloro-4-[methyl-(1-methyl-pyrrolidin-3-yl)-amino]-phenyl}-thioureido)-phenyl]-2,6-difluoro-benzamide350 427 Pyridine-2-carboxylic acid{4-[3-(3-chloro-4-dimethylamino-phenyl)-thioureido]-phenyl}-amide 351430 Pyridine-2-carboxylic acid{4-[3-(3-chloro-4-methylsulfanyl-phenyl)-thioureido]-phenyl}-amide 352428 Pyridine-2-carboxylic acid{4-[3-(5-chloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-amide 353417 Furan-2-carboxylic acid{4-[3-(5-chloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-amide 354496 Pyridine-2-carboxylic acid[4-(3-{3-chloro-4-[methyl-(1-methyl-pyrrolidin-3-yl)-amino]-phenyl}-thioureido)-phenyl]-amide355 495N-{3-Chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureidol-phenyl}-2-fluoro-benzamide356 467 Furan-2-carboxylic acid{3-chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide357 515N-{4-[3-(3-Chloro-4-cyclohexylsulfanyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide358 449N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-trifluoromethyl-phenyl}-acetamide359 529N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-trifluoromethyl-phenyl}-2-fluoro-benzamide360 421N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2-dimethyl-amino-acetamide361 473 Furan-2-carboxylic acid(4-{3-[3-chloro-4-(2-dimethylamino-acetylamino)-phenyl]-thioureido}-phenyl)-amide362 501N-(4-{3-[3-Chloro-4-(2-dimethylamino-acetylamino)-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide363 461N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl)-2-piperidin-1-yl-acetamide364 541N-(4-{3-[3-Chloro-4-(2-piperidin-1-yl-acetylamino)-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide365 513 Furan-2-carboxylic acid(4-{3-[3-chloro-4-(2-piperidin-1-yl-acetylamino)-phenyl]-thioureido}-phenyl)-amide366 463N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2-morpholin-4-yl-acetamide367 543N-(4-{3-[3-Chloro-4-(2-morpholin-4-yl-acetylamino)-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide368 515 Furan-2-carboxylic acid(4-{3-[3-chloro-4-(2-morpholin-4-yl-acetylamino)-phenyl]-thioureido]-phenyl)-amide369 414N-{4-[3-(3-Chloro-4-methanesulfonylamino-phenyl)-thioureido]-phenyl}-acetamide370 494N-{4-[3-(3-Chloro-4-methanesulfonylamino-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide371 466 Furan-2-carboxylic acid{4-[3-(3-chloro-4-methanesulfonylamino-phenyl)-thioureido]-phenyl}-amide372 481N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2-(2-dimethy-lamino-ethylsulfanyl)-acetamide373 561N-[4-(3-{3-Chloro-4-[2-(2-dimethylamino-ethylsulfanyl)-acetylamino]-phenyl}-thioureido)-phenyl]-2-fluoro-benzamide374 585N-[4-(3-{4-[(1-Benzyl-pyrrolidin-3-yl)-methyl-amino]-3-chloro-phenyl}-thioureido)-phenyl]-2-methyl-benzamide375 523N-[4-(3-{3-Chloro-4-[methyl-(1-methyl-piperidin-4-yl)-amino]-phenyl)}-thioureido)-phenyl]-2-methyl-benzamide376 510 Pyridine-2-carboxylic acid[4-(3-{3-chloro-4-[methyl-(1-methyl-piperidin-4-yl)-amino]-phenyl}-thioureido)-phenyl]-amide377 347 N-{4-[3-(3-Chloro-4-vinyl-phenyl)-thioureido]-phenyl}-acetamide378 441 Furan-2-carboxylic acid{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 379452 Pyridine-2-carboxylic acid{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 380487N-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-2,6-difluoro-benzamide381 486N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-cyano-phenyl}-2-fluoro-benzamide382 458 Furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-cyano-phenyl}-amide383 406N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-cyano-phenyl}-acetamide384 395N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-2-methyl-isothioureido]-phenyl}-acetamide385 396N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-2-methyl-isothioureido]-phenyl}-acetamide386 461N-{4-[3-(3-Chloro-4-ethylsulfanyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide387 489N-{4-[3-(4-Butylsulfanyl-3-chloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide388 411N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methoxy-phenyl}-acetamide389 491N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methoxy-phenyl}-2-fluoro-benzamide390 463 Furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methoxy-phenyl}-amide391 531 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[3-chloro-4-(2-piperidin-1-yl-acetyl-amino)-phenyl]-thioureido}-phenyl)-amide392 481N-{4-[3-(3-Chloro-4-methanesulfinyl-phenyl)-thioureido]-phenyl}-2,6-difluoro-benzamide393 497N-{4-[3-(3-Chloro-4-methanesulfonyl-phenyl)-thioureido]-phenyl}-2,6-difluoro-benzamide394 459N-{4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)-thioureido]-2-methyl-phenyl}-2-fluoro-benzamide395 429N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]-2-methyl-phenyl}-2-fluoro-benzamide396 533 Furan-2-carboxylic acid[4-(3-{3-chloro-4-[2-(2-dimethylamino-ethylsulfanyl)-acetylamino]-phenyl}-thioureido)-phenyl]-amide397 458N-{4-[3-(4-Acetylamino-3-chloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide398 460[2-Chloro-4-(3-{4-[(furan-2-carbonyl)-amino]-phenyl}-thioureido)-phenyl]-carbamicacid ethyl ester 399 488(2-Chloro-4-{3-[4-(2-fluoro-benzoylamino)-phenyl]-thioureido}-phenyl)-carbamicacid ethyl ester 400 440N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-benzamide401 520N-{4-[({[4-(Benzoylamino)-3-chloro-phenyl]-amino}-thioxomethyl)-amino]-phenyl}-2-fluoro-benzamide402 529N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-trifluoromethyl-phenyl}-2-fluoro-benzamide403 492 Furan-2-carboxylic acid{4-[3-(4-benzoylamino-3-chloro-phenyl)-thioureido]-phenyl}-amide 404 416N-{4-[3-(4-Amino-3-chloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide405 479N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2-thiomorphin-4-yl-acetamide406 531 Furan-2-carboxylic acid(4-{3-[3-chloro-4-(2-thiomorpholin-4-yl-acetylamino)-phenyl]-thioureido}-phenyl)-amide407 559N-(4-{3-[3-Chloro-4-(2-thiomorpholin-4-yl-acetylamino)-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide408 461N-{4-[3-(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]-2-methyl-phenyl}-2-fluoro-benzamide409 430 Furan-2-carboxylic acid{4-[3-(4-acetylamino-3-chloro-phenyl)-thioureido]-phenyl}-amide 410 477N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2-dipropylamino-acetamide411 529 Furan-2-carboxylic acid(4-{3-[3-chloro-4-(2-dipropylamino-acetylamino)-phenyl]-thioureido}-phenyl)-amide412 449N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2-diethyl-amino-acetamide413 501 Furan-2-carboxylic acid(4-{3-[3-chloro-4-(2-diethylamino-acetylamino)-phenyl]-thioureido}-phenyl)-amide414 529N-(4-{3-[3-Chloro-4-(2-diethylamino-acetylamino)-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide415 447N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2-pyrrolidin-1-yl-acetamide416 499 Furan-2-carboxylic acid(4-{3-[3-chloro-4-(2-pyrrolidin-1-yl-acetylamino)-phenyl]-thioureido}-phenyl)-amide417 527N-(4-{3-(3-[3-Chloro-4-(2-pyrrolidin-1-yl-acetylamino)-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide418 475N-{4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)-thioureido]-3-methoxy-phenyl}-2-fluoro-benzamide419 445N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]-3-methoxy-phenyl}-2-fluoro-benzamide420 477N-{4-[3-(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]-3-methoxy-phenyl}-2-fluoro-benzamide421 388 Furan-2-carboxylic acid{4-[3-(4-amino-3-chloro-phenyl)-thioureido]-phenyl}-amide 422 527Furan-2-carboxylic acid(4-{3-[4-(2-azepan-1-yl-acetylamino)-3-chloro-phenyl]-thioureido}-phenyl)-amide423 555N-(4-{3-[4-(2-Azepan-1-yl-acetylamino)-3-chloro-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide424 527 Furan-2-carboxylic acid[4-(3-{3-chloro-4-[2-(2-methyl-piperidin-1-yl)-acetyl-amino]-phenyl}-thioureido)-phenyl]-amide425 555N-[4-(3-{3-Chloro-4-[2-(2-methyl-piperidin-1-yl)-acetylamino]-phenyl}-thioureido)-phenyl]-2-fluoro-benzamide426 339 Furan-2-carboxylic acid[4-(3-pyridin-2-yl-thioureido)-phenyl]-amide 427 339 Furan-2-carboxylicacid [4-(3-pyridin-4-yl-thioureido)-phenyl]-amide 428 3672-Fluoro-N-[4-(3-pyridin-3-yl-thioureido)-phenyl]-benzamide 429 339Furan-2-carboxylic acid [4-(3-pyridin-3-yl-thioureido)-phenyl]-amide 430353 Furan-2-carboxylic acid{4-[3-(3-amino-phenyl)-thioureido]-phenyl}-amide 431 406Furan-2-carboxylic acid{4-[3-(3-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 432 3802-Fluoro-N-[4-(3-m-tolyl-thioureido)-phenyl]-benzamide 433 4342-Fluoro-N-{4-[3-(3-trifluoromethyl-phenyl)-thioureido]-phenyl}-benzamide434 381 N-{4-[3-(3-Amino-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide435 388 Furan-2-carboxylic acid{4-[3-(3-amino-5-chloro-phenyl)-thioureido]-phenyl}-amide 436 352Furan-2-carboxylic acid [4-(3-m-tolyl-thioureido)-phenyl]-amide 437 416N-{4-[3-(2-Amino-5-chloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide438 571(2-Chloro-4-{3-[4-(2-fluoro-benzoylamino)-phenyl]-thioureido}-phenyl)-carbamicacid 2-piperidin-1-yl-ethyl ester 439 543[2-Chloro-4-(3-{4-[(furan-2-carbonyl)-amino]-phenyl}-thioureido)-phenyl]-carbamicacid 2-piperidin-1-yl-ethyl ester 440 388 Furan-2-carboxylic acid{4-[3-(2-amino-5-chloro-phenyl)-thioureido]-phenyl}-amide 441 363Furan-2-carboxylic acid {4-[3-(3-cyano-phenyl)-thioureido]-phenyl}-amide442 416N-{4-[3-(3-Amino-5-chloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide443 367 2-Fluoro-N-[4-(3-pyridin-2-yl-thioureido)-phenyl]-benzamide 444367 2-Fluoro-N-[4-(3-pyridin-4-yl-thioureido)-phenyl]-benzamide 445 374Furan-2-carboxylic acid{4-[3-(6-chloro-pyridin-3-yl)-thioureido]-phenyl}-amide 446 388Furan-2-carboxylic acid{4-[3-(2-amino-3-chloro-phenyl)-thioureido]-phenyl}-amide 447 396Furan-2-carboxylic acid{4-[3-(3-hydrazinocarbonyl-phenyl)-thioureido]-phenyl}-amide 448 4102-Fluoro-N-(4-{3-[3-(1-hydroxy-ethyl)-phenyl]-thioureido}-phenyl)-benzamide449 414 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-hydrazinocarbonyl-phenyl)-thioureido]-phenyl}-amide 450 399[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-isopropyl-phenyl)-thioureido]-phenyl}-amide 451 380Furan-2-carboxylic acid{4-[3-(3-isopropyl-phenyl)-thioureido]-phenyl}-amide 452 4092-Fluoro-N-{4-[3-(3-isopropyl-phenyl)-thioureido]-phenyl}-benzamide 453381 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-cyano-phenyl)-thioureido]-phenyl}-amide 454 410N-{4-[3-(3-Dimethylamino-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide455 381 Furan-2-carboxylic acid{4-[3-(3-dimethylamino-phenyl)-thioureido]-phenyl}-amide 456 370[1,2,3]Thiadiazole-4-carboxylic acid[4-(3-m-tolyl-thioureido)-phenyl]-amide 457 424[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 458 479N-{3-Chloro-4-[3-(5-chloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide459 449N-{3-Chloro-4-[3-(3-chloro-4-methyl-phenyl)-thioreido]-phenyl}-2-fluoro-benzamide460 481N-{3-Chloro-4-[3-(3-chloro-4-methylsulfanyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide461 391 N-{4-[3-(3-Cyano-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide462 395 Furan-2-carboxylic acid{4-[3-(3-acetylamino-phenyl)-thioureido]-phenyl}-amide 463 4242-Fluoro-N-{4-[3-(3-hydrazinocarbonyl-phenyl)-thioureido]-phenyl}-benzamide464 400 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[3-(1-hydroxy-ethyl)-phenyl]-thioureido}-phenyl)-amide 465 434N-{4-[3-(2-Amino-3-chloro-phenyl)-thioureido]-phenyl}-2,6-difluoro-benzamide466 406 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-amino-5-chloro-phenyl)-thioureido]-phenyl}-amide 467 398Furan-2-carboxylic acid{4-[3-(3,5-dimethoxy-phenyl)-thioureido]-phenyl}-amide 468 416[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,5-dimethoxy-phenyl)-thioureido]-phenyl}-amide 469 4545-(3-{4-[(Furan-2-carbonyl)-amino]-phenyl}-thioureido)-isophthalic aciddimethyl ester 470 434 Isoxazole-5-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 471 392[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(6-chloro-pyridin-3-yl)-thioureido]-phenyl)-amide 472 382Furan-2-carboxylic acid(4-{3-[3-(1-hydroxy-ethyl)-phenyl]-thioureido}-phenyl)-amide 473 368Furan-2-carboxylic acid{4-[3-(3-methoxy-phenyl)-thioureido]-phenyl}-amide 474 354Furan-2-carboxylic acid{4-[3-(3-hydroxy-phenyl)-thioureido]-phenyl}-amide 475 3822-Fluoro-N-{4-[3-(3-hydroxy-phenyl)-thioureido]-phenyl}-benzamide 4763962-Fluoro-N-{4-[3-(3-hydroxymethyl-phenyl)-thioureido]-phenyl}-benzamide477 423N-{4-[3-(3-Acetylamino-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide478 413 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-acetylamino-phenyl)-thioureido]-phenyl}-amide 479 400[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-dimethylamino-phenyl)-thioureido]-phenyl}-amide 480 340Furan-2-carboxylic acid [4-(3-pyrimidin-4-yl-thioureido)-phenyl]-amide481 378 Furan-2-carboxylic acid{4-[3-(1H-indazol-5-yl)-thioureido]-phenyl}-amide 482 395Furan-2-carboxylic acid[4-(3-benzothiazol-5-yl-thioureido)-phenyl]-amide 483 4062-Fluoro-N-{4-[3-(1H-indazol-5-yl)-thioureido]-phenyl}-benzamide 484 424N-[4-(3-Benzothiazol-5-yl-thioureido)-phenyl]-2-fluoro-benzamide 485 4735-(3-{4-[([1,2,3]Thiadiazole-4-carbonyl)-amino]-phenyl}-thioureido)-isophthalicacid dimethyl ester 486 442 Furan-2-carboxylic acid(4-{3-[4-(1-azido-ethyl)-3-chloro-phenyl]-thioureido}-phenyl)-amide 487396 2-Fluoro-N-{4-[3-(3-methoxy-phenyl)-thioureido]-phenyl}-benzamide488 368 Furan-2-carboxylic acid{4-[3-(3-hydroxymethyl-phenyl)-thioureido]-phenyl}-amide 489 416Furan-2-carboxylic acid{4-[3-(5-chloro-2-dimethylamino-phenyl)-thioureido]-phenyl}-amide 490444N-{4-[3-(5-Chloro-2-dimethylamino-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide491 506[3-Chloro-5-(3-{4-[([1,2,3]thiadiazole-4-carbonyl)-amino]-phenyl}-thioureido)-phenyl]-carbamicacid tert-butyl ester 492 470N-(4-{3-[4-(1-Azido-ethyl)-3-chloro-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide493 337 Furan-2-carboxylic acid[4-(1H-thiazolo[5,4-b]pyridin-2-ylideneamino)-phenyl]-amide 494 378Furan-2-carboxylic acid{4-[3-(1H-benzoimidazol-5-yl)-thioureido]-phenyl}-amide 495 392Furan-2-carboxylic acid{4-[3-(2-methyl-1H-benzoimidazol-5-yl)-thioureido]-phenyl}-amide 496 406N-{4-[3-(1H-Benzoimidazol-5-yl)-thioureido]-phenyl}-2-fluoro-benzamide497 4202-Fluoro-N-{4-[3-(2-methyl-1H-benzoimidazol-5-yl)-thioureido]-phenyl}-benzamide498 452 [1,2,3]Thiadiazole-4-carboxylic acid{5-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-2-yl}-amide499 445 Pyridine-2-carboxylic acid{5-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-2-yl}-amide500 434 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(5-chloro-2-dimethylamino-phenyl)-thioureido]-phenyl}-amide 501484 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[4-(2-amino-pyrimidin-4-yl)-3-chloro-phenyl]-thioureido}-phenyl)-amide502 494N-(4-{3-[4-(2-Amino-pyrimidin-4-yl)-3-chloro-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide503 434 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-chloro-2-dimethylamino-phenyl)-thioureido]-phenyl}-amide 504462N-{4-[3-(3-Chloro-2-dimethylamino-phenyl)-thioureido]-phenyl}-2,6-difluoro-benzamide505 416 Furan-2-carboxylic acid{4-[3-(3-chloro-2-dimethylamino-phenyl)-thioureido]-phenyl}-amide 506445 Pyridine-2-carboxylic acid{6-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl}-amide507 462N-{6-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl}-2-fluoro-benzamide508 482 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-iodo-phenyl)-thioureido]-phenyl}-amide 509 413[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-tert-butyl-phenyl)-thioureido]-phenyl}-amide 510 387Furan-2-carboxylic acid{4-[3-(3-chloro-benzyl)-thioureido]-phenyl}-amide 511 415N-{4-[3-(3-Chloro-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide 512 434Furan-2-carboxylic acid{6-[3-(5-chloro-2,4-dimethoxy-phenyl}-thioureido]-pyridin-3-yl}-amide513 435 [1,2,3]Thiadazole-4-carboxylic acid{4-[3-(3-bromo-phenyl)-thioureido]-phenyl}-amide 514 452[1,2,3]Thiadiazole-4-carboxylic acid{6-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl}-amide515 426 [1,2,3]Thiadiazole-4-carboxylic acid{5-[3-(3,5-dichloro-phenyl)-thioureido]-pyridin-2-yl}-amide 516 474Furan-2-carboxylic acid{4-[3-(3,5-bis-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 517 502N-{4-[3-(3,5-Bis-trifluoromethyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide518 450N-{4-[3-(4-Amino-3,5-dichloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide519 539N-{4-[3-(4-Amino-3,5-dibromo-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide520 392 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(5-chloro-pyridin-3-yl)-thioureido]-phenyl}-amide 521 529[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-amino-3,5-dibromo-phenyl)-thioureido]-phenyl}-amide 522 434[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-chloro-5-dimethylamino-phenyl)-thioureido]-phenyl}-amide 523444N-{4-[3-(3-Chloro-5-dimethylamino-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide524 416 Furan-2-carboxylic acid{4-[3-(3-chloro-5-dimethylamino-phenyl)-thioureido]-phenyl}-amide 525436 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(5-bromo-pyridin-3-yl)-thioureido]-phenyl}-amide 526 379Furan-2-carboxylic acid{4-[3-(1H-benzotriazol-5-yl)-thioureido]-phenyl}-amide 527 425N-{4-[3-(1H-Benzotriazol-5-yl)-thioureido]-phenyl}-2,6-difluoro-benzamide528 388N-[4-({[2-(3-Chloro-phenyl)-hydrazino]-thioxomethyl}-amino)-phenyl]-furan-2-carboxamide529 416N-[4-({[2-(3-Chloro-phenyl)-hydrazino]-thioxomethyl}-amino)-phenyl]-2-fluoro-benzamide530 456 Furan-2-carboxylic acid{4-[3-(2-amino-3-chloro-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide531 513N-{4-[3-(3-Bromo-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide532 503 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-bromo-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 533374 {4-[(Furan-2-carbonyl)-amino]-phenyl}-thiocarbamic acidO-(3-chloro-phenyl)ester 534 474 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(2-amino-3-chloro-5-trifluoro-methyl-phenyl)-thioureido]-phenyl}-amide535 508 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-piperidin-1-yl-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide536 380 N-[4-(3-Benzyl-thioureido)-phenyl]-2-fluoro-benzamide 537 439[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,4-dichloro-benzyl)-thioureido]-phenyl}-amide 538 449N-{4-[3-(3,4-Dichloro-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide 539370 [1,2,3]Thiadiazole-4-carboxylic acid[4-(3-benzyl-thioureido)-phenyl]-amide 540 424N-[4-(3-Benzo[1,3]dioxol-5-ylmethyl-thioureido)-phenyl]-2-fluoro-benzamide541 414 [1,2,3]Thiadiazole-4-carboxylic acid[4-(3-benzo[1,3]dioxol-5-ylmethyl-thioureido)-phenyl]-amide 542 506[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,5-bis-trifluoromethyl-benzyl)-thioureido]-phenyl}-amide 543 516N-{4-[3-(3,5-Bis-trifluoromethyl-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide544 352 Furan-2-carboxylic acid [4-(3-benzyl-thioureido)-phenyl]-amide545 421 Furan-2-carboxylic acid{4-[3-(3,4-dichloro-benzyl)-thioureido]-phenyl}-amide 546 396Furan-2-carboxylic acid[4-(3-benzo[1,3]dioxol-5-ylmethyl-thioureido)-phenyl]-amide 547 488Furan-2-carboxylic acid{4-[3-(3,5-bis-trifluoromethyl-benzyl)-thioureido]-phenyl}-amide 548 503[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-bromo-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 549529N-{4-[3-(3-Bromo-4-trifluoromethoxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide550 519 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-bromo-4-trifluoromethoxy-phenyl)-thioureido]-phenyl}-amide 551473 Furan-2-carboxylic acid{4-[3-(3-chloro-4-trifluoromethylsulfanyl-phenyl)-thioureido]-phenyl}-amide552 4122-Fluoro-N-(4-{3-[2-(3-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide553 4122-Fluoro-N-(4-{3-[2-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide554 402 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 555 402[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 556 495[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[3-(2-methyl-butyl)-5-trifluoro-methyl-phenyl]-thioureido}-phenyl)-amide557 481 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-isobutyl-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide558 523 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[3-(4-methyl-piperazin-1-yl)-5-trifluoro-methyl-phenyl]-thioureido}-phenyl)-amide559 510 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-morpholin-4-yl-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide560 494 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-pyrrolidin-1-yl-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide561 384 Furan-2-carboxylic acid(4-{3-[2-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 562 419[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3-chloro-phenyl)-ethyl]-thioureido}-phenyl)-amide 563 429N-(4-{3-[2-(3-Chloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide564 401 Furan-2-carboxylic acid(4-{3-[2-(3-chloro-phenyl)-ethyl]-thioureido}-phenyl)-amide 565 402[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 566 5042-Fluoro-N-(4-[3-(3-pyrrolidin-1-yl-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-benzamide567 477N-{4-[3-(3-Dimethylamino-5-trifluoromethyl-phenyl)-thioureido]-phenyl)-2-fluoro-benzamide568 5202-Fluoro-N-{4-[3-(3-morpholin-4-yl-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-benzamide569 5332-Fluoro-N-(4-{3-[3-(4-methyl-piperazin-1-yl)-5-trifluoromethyl-phenyl]-thioureido}-phenyl)-benzamide570 5182-Fluoro-N-{4-[3-(3-piperidin-1-yl-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-benzamide571 468 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-dimethylamino-5-trifluoromethyl]-phenyl)-thioureido]-phenyl}-amide572 405 [1,2,3]Thadiazole-4-carboxylic acid{4-[3-(3-chloro-benzyl)-thioureido]-phenyl}-amide 573 384Furan-2-carboxylic acid(4-{3-[2-(3-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 574 366Furan-2-carboxylic acid [4-(3-phenethyl-thioureido)-phenyl]-amide 575384 [1,2,3]Thiadiazole-4-carboxylic acid[4-(3-phenethyl-thioureido)-phenyl]-amide 576 3942-Fluoro-N-[4-(3-phenethyl-thioureido)-phenyl]-benzamide 577 5052-Fluoro-N-(4-{3-[3-(2-methyl-butyl)-5-trifluoromethyl-phenyl]-thioureido}-phenyl)-benzamide578 4912-Fluoro-N-{4-[3-(3-isobutyl-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-benzamide579 388 Furan-2-carboxylic acid{4-[3-(3,5-difluoro-benzyl)-thioureido]-phenyl}-amide 580 416N-{4-[3-(3,5-Difluoro-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide 581406 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,5-difluoro-benzyl)-thioureido]-phenyl}-amide 582 421Furan-2-carboxylic acid{4-[3-(3,5-dichloro-benzyl)-thioureido]-phenyl}-amide 583 449N-{4-[3-(3,5-Dichloro-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide 584439 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,5-dichloro-benzyl)-thioureido]-phenyl}-amide 585 438Furan-2-carboxylic acid{4-[3-(3-fluoro-5-trifluoromethyl-benzyl)-thioureido]-phenyl}-amide 5864662-Fluoro-N-{4-[3-(3-fluoro-5-trifluoromethyl-benzyl)-thioureido]-phenyl}-benzamide587 456 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-fluoro-5-trifluoromethyl-benzyl)-thioureido]-phenyl}-amide 588384 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(1-phenyl-ethyl)-thioureido]-phenyl}-amide 589 3942-Fluoro-N-{4-[3-(1-phenyl-ethyl)-thioureido]-phenyl}-benzamide 590 366Furan-2-carboxylic acid {4-[3-(1-phenyl-ethyl)-thioureido]-phenyl}-amide591 4122-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide592 384 Furan-2-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 593 413N-{4-[3-(1-tert-Butyl-1H-imidazole-2-yl)-thioureido]-phenyl}-2-fluoro-benzamide594 510 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[3-(isobutyl-methyl-amino)-5-trifluorometbyl-phenyl]-thioureido}-phenyl)-amide595 510 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[3-(3-hydroxy-pyrrolidin-1-yl)-5-trifluoromethyl-phenyl]-thioureido}-phenyl)-amide596 5202-Fluoro-N-(4-{3-[3-(isobutyl-methyl-amino)-5-trifluoromethyl-phenyl]-thioureido}-phenyl)-benzamide597 510 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[3-(butyl-methyl-amino)-5-trifluoromethyl-phenyl]-thioureido}-phenyl)-amide598 520N-(4-{3-[3-(Butyl-methyl-amino)-5-trifluoromethyl-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide599 520 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide600 442 [1,2,3]Thiadiazole-4-carboxyiic acid{4-[3-(4-fluoro-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 601522 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-piperidin-1-yl-3-trifluoromethyl-benzyl)-thioureido]-phenyl-amide602 482 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-dimethylamino-3-trifluoromethyl-benzyl)-thioureido]-phenyl}-amide603 381 Furan-2-carboxylic acid(4-{3-[2-(4-amino-phenyl)-ethyl]-thioureido}-phenyl)-amide 604 445Furan-2-carboxylic acid(4-{3-[2-(4-bromo-phenyl)-ethyl]-thioureido}-phenyl)-amide 605 380Furan-2-carboxylic acid{4-[3-(2-p-tolyl-ethyl)-thioureido]-phenyl}-amide 606 463[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(4-bromo-phenyl)-ethyl]-thioureido}-phenyl)-amide 607 396Furan-2-carboxylic acid(4-{3-[2-(3-methoxy-phenyl)-ethyl]-thioureido}-phenyl)-amide 608 403[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(1-tert-butyl-1H-imidazol-2-yl)-thioureido]-phenyl}-amide 609 384Furan-2-carboxylic acid{4-[3-(1-tert-butyl-1H-imidazol-2-yl)-thioureido]-phenyl}-amide 610 492N-{4-[3-(4-Dimethylamino-3-trifluoromethyl-benzyl)-thioureido]-phenyl)-2-fluoro-benzamide611 427 Furan-2-carboxylic acid(4-{3-[2-(3,4-dimethoxy-phenyl)-ethyl]-thioureido}-phenyl)-amide 612 380Furan-2-carboxyiic acid{4-[3-(3-phenyl-propyl)-thioureido]-phenyl}-amide 613 399[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-phenyl-propyl)-thioureido]-phenyl}-amide 614 502Furan-2-carboxylic acid(4-{3-[2-(3,5-bis-trifluoromethyl-phenyl)-ethy1]-thioureido}-phenyl)-amide615 550 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-iodo-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 6165322-Fluoro-N-{4-[3-(4-piperidin-1-yl-3-trifluoromethyl-benzyl)-thioureido]-phenyl}-benzamide617 537 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[4-(4-methyl-piperazin-1-yl)-3-trifluoromethyl-benzyl]-thioureido}-phenyl)-amide618 482 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-dimethylamino-5-trifluoromethyl-benzyl)-thioureido]-phenyl}amide619 488 Furan-2-carboxylic acid{4-[3-(3,5-bis-trifluoromethyl-phenyl)-thioureido-methyl]-phenyl}-amide620 421 Furan-2-carboxylic acid{4-[3-(3,5-dichloro-phenyl)-thioureidomethyl]-phenyl}-amide 621 421Furan-2-carboxylic acid{4-[3-(3,4-dichloro-phenyl)-thioureidomethyl]-phenyl}-amide 622 455Furan-2-carboxylic acid{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-thioureido-methyl]-phenyl}-amide623 4662-Fluoro-N-{4-[3-(4-fluoro-3-trifluoromethyl-benzyl)-thioureido]-phenyl}-benzamide624 456 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-fluoro-3-trifluoromethyl-benzyl)-thioureido]-phenyl}-amide 625410 2-Fluoro-N-{4-[3-(2-phenoxy-ethyl)-thioureido]-phenyl}-benzamide 626382 Furan-2-carboxylic acid{4-[3-(2-phenoxy-ethyl)-thioureido]-phenyl}-amide 627 400[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(2-phenoxy-ethyl)-thioureido]-phenyl}-amide 628 4092-Fluoro-N-{4-[3-(3-phenyl-propyl)-thioureido]-phenyl}-benzamide 629 425[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(5-trifluoromethyl-pyridin-3-yl)-thioureido]-phenyl}-amide 630 439[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,4-dichloro-phenyl)-thioureido-methyl]-phenyl}-amide 631 473[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-thioureidomethyl]-phenyl}-amide632 3812-Fluoro-N-[4-(3-pyridin-3-ylmethyl-thioureido)-phenyl]-benzamide 633353 Furan-2-carboxylic acid[4-(3-pyridin-3-ylmethyl-thioureido)-phenyl]-amide 634 371[1,2,3]Thiadiazole-4-carboxylic acid[4-(3-pyridin-3-ylmethyl-thioureido)-phenyl]-amide 635 439[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,5-dichloro-phenyl)-thioureido-methyl]-phenyl}-amide 636 492N-{4-[3-(3-Dimethylamino-5-trifluoromethyl-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide637 415 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3-methoxy-phenyl)-ethyl]-thioureido}-phenyl)-amide 638 399[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(2-p-tolyl-ethyl)-thioureido]-phenyl}-amide 639 445[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3,4-dimethoxy-phenyl)-ethyl]-thioureido}-phenyl)-amide 640 506[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,5-bis-trifluoromethyl-phenyl)-thioureidomethyl]-phenyl}-amide641 516N-{4-[3-(3,5-Bis-trifluoromethyl-phenyl)-thioureidomethyl]-phenyl}-2-fluoro-benzamide642 449N-{4-[3-(3,5-Dichloro-phenyl)-thioureidomethyl]-phenyl}-2-fluoro-benzamide643 449N-{4-[3-(3,5-Dichloro-phenyl)-thioureidomethyl]-phenyl}-2-fluoro-benzamide644 448 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-acetylamino-5-chloro-phenyl)-thioureido]-phenyl}-amide 645 453[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3,4-dichloro-phenyl)-ethyl]-thioureido}-phenyl)-amide 646 413[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(1-methyl-3-phenyl-propyl)-thioureido]-phenyl}-amide 647 463[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[1-(4-bromo-phenyl)-ethyl]-thioureido}-phenyl)-amide 648 413[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-phenyl-butyl)-thioureido]-phenyl}-amide 649 397[1,2,3]Thiadiazole-4-carboxylic acid[4-(3-indan-1-yl-thioureido)-phenyl]-amide 650 400[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(2-methoxy-benzyl)-thioureido]-phenyl}-amide 651 415[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(2-methoxy-phenyl)-ethyl]-thioureido}-phenyl)-amide 652 415[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(4-methoxy-phenyl)-ethyl]-thioureido}-phenyl)-amide 653 506N-(4-{3-[2-(3-Dimethylamino-5-trifluoromethyl-phenyl)-ethyl]-thioureido]-phenyl}-2-fluoro-benzamide654 510 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[3-(3-dimethylamino-propyl)-5-trifluoromethyl-phenyl]-thioureido}-phenyl)-amide655 417 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(2-phenylsulfanyl-ethyl)-thioureido]-phenyl}-amide 656 4272-Fluoro-N-{4-[3-(2-phenylsulfanyl-ethyl)-thioureido]-phenyl}-benzamide657 399 Furan-2-carboxylic acid{4-[3-(2-phenylsulfanyl-ethyl)-thioureido]-phenyl}-amide 658 3812-Fluoro-N-[4-(3-pyridin-4-ylmethyl-thioureido)-phenyl]-benzamide 659353 Furan-2-carboxylic acid[4-(3-pyridin-4-ylmethyl-thioureido)-phenyl]-amide 660 371[1,2,3]Thiadiazole-4-carboxylic acid[4-(3-pyridin-4-ylmethyl-thioureido)-phenyl]-amide 661 5062-Fluoro-N-{4-[3-(3-iodo-benzyl)-thioureido}-benzamide 662 478Furan-2-carboxylic acid {4-[3-(3-iodo-benzyl)-thioureido]-phenyl}-amide663 496 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-iodo-benzyl)-thioureido]-phenyl}-amide 664 479N-(4-}3-[2-(3,5-Dichloro-phenoxy)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide665 451 Furan-2-carboxylic acid(4-{3-[2-(3,5-dichloro-phenoxy)-ethyl]-thioureido}-phenyl)-amide 666 445N-(4-{3-[2-(3-Chloro-phenoxy)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide667 417 Furan-2-carboxylic acid(4-{3-[2-(3-chloro-phenoxy)-ethyl]-thioureido}-phenyl)-amide 668 435[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3-chloro-phenoxy)-ethyl]-thioureido}-phenyl)-amide 669 4662-Fluoro-N-{4-[3-(2-fluoro-5-trifluoromethyl-benzyl)-thioureido]-phenyl}-benzamide670 438 Furan-2-carboxylic acid{4-[3-(2-fluoro-5-trifluoromethyl-benzyl)-thioureido]-phenyl}-amide 671456 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(2-fluoro-5-trifluoromethyl-benzyl)-thioureido]-phenyl}-amide 672416 N-{4-[3-(3,4-Difluoro-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide673 452N-(4-{3-[2-(4-Dimethylamino-3-methyl-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide674 496 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3-dimethylamino-5-trifluoro-methyl-phenyl)-ethyl]-thioureido}-phenyl)-amide675 388 Furan-2-carboxylic acid{4-[3-(3,4-difluoro-benzyl)-thioureido]-phenyl}-amide 676 406[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,4-difluoro-benzyl)-thioureido]-phenyl}-amide 677 433N-{4-[3-(3-Chloro-4-fluoro-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide678 495 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3-bromo-phenylsulfanyl)-ethyl]-thioureido}-phenyl)-amide 679477 Furan-2-carboxylic acid(4-{3-[2-(3-bromo-phenylsulfanyl)-ethyl]-thioureido}-phenyl)-amide 680505N-(4-{3-[2-(3-Bromo-phenylsulfanyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide681 493 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3-bromo-4-methoxy-phenyl)-ethyl]-thioureido}-phenyl)-amide 682493 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(5-bromo-2-methoxy-phenyl)-ethyl]-thioureido}-phenyl)-amide 683419 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(2-chloro-phenyl)-ethyl]-thioureido}-phenyl)-amide 684 402[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(2-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 685 419[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(4-chloro-phenyl)-ethyl]-thioureido}-phenyl)-amide 686 475[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,3-diphenyl-propyl)-thioureido]-phenyl}-amide 687 5472-Fluoro-N-(4-{3-[4-(4-methyl-piperazin-1-yl)-3-trifluoromethyl-benzyl]-thioureido}-phenyl)-benzamide688 469 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3,5-dichloro-phenoxy)-ethyl]-thioureido}-phenyl)-amide 689 423[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-chloro-4-fluoro-benzyl)-thioureido]-phenyl}-amide 690 427[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-tert-butyl-benzyl)-thioreido]-phenyl}-amide 691 399[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,5-dimethyl-benzyl)-thioureido]-phenyl}-amide 692 442[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(4-dimethylamino-3-methyl-phenyl)-ethy1]-thioureido}-phenyl)-amide693 479 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(4-bromo-phenoxy)-ethyl]-thioureido}-phenyl)-amide 694 526[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(4-iodo-phenoxy)-ethyl]-thioureido}-phenyl)-amide 695 489N-(4-{3-[2-(4-Bromo-phenoxy)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide696 5362-Fluoro-N-(4-{3-[2-(4-iodo-phenoxy)-ethyl]-thioureido}-phenyl)-benzamide697 461 Furan-2-carboxylic acid(4-{3-[2-(4-bromo-phenoxy)-ethyl]-thioureido}-phenyl)-amide 698 508Furan-2-carboxylic acid(4-{3-[2-(4-iodo-phenoxy)-ethyl]-thioureido}-phenyl)-amide 699 408Oxazole-4-carboxylic acid{4-[3-(3,4-dichloro-phenyl)-thioureido]-phenyl}-amide 700 424Thiazole-4-carboxylic acid{4-[3-(3,5-dichloro-phenyl)-thioureido]-phenyl}-amide 701 491Thiazole-4-carboxylic acid{4-[3-(3,5-bis-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 702 408Oxazole-4-carboxylic acid{4-[3-(3,5-dichloro-phenyl)-thioureido]-phenyl}-amide 703 469[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3,4-dichloro-phenoxy)-ethyl]-thioureido}-phenyl)-amide 704 424Thiazole-4-carboxylic acid{4-[3-(3,4-dichloro-phenyl)-thioureido]-phenyl}-amide 705 458Thiazole-4-carboxylic acid{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 706400 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(2-phenylamino-ethyl)-thioureido]-phenyl}-amide 707 453[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(2,4-dichloro-phenyl)-ethyl]-thioureido}-phenyl)-amide 708 452[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide 709453 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(2,6-dichloro-phenyl)-ethyl]-thioureido}-phenyl)-amide 710 485[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3,4-dichloro-phenylsulfanyl)-ethyl]-thioureido}-phenyl)-amide711 503 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(2-fluoro-5-trifluoromethylphenylsulfanyl)-ethyl]-thioureido}-phenyl)-amide712 668N-(4-{3-[3-Chloro-5-(3-{4-[([1,2,3]thiadiazole-4-carbonyl)-amino]-phenyl}-thioureido)-phenyl]-thioureido}-phenyl)-[1,2,3]thiadiazole-4-carboxamide 713 413 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(4-ethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide 714 442Oxazole-4-carboxylic acid{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 715475 Oxazole-4-carboxylic acid{4-[3-(3,5-bis-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 716 420[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3,4-difluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 717 452[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(4-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide 718435 Furan-2-carboxylic acid(4-{3-[2-(3,4-dichloro-phenyl)-ethyl]-thioureido}-phenyl)-amide 719 463N-(4-{3-[2-(3,4-Dichloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide720 420 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3,5-difluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 721 4122-Fluoro-N-(4-{3-[2-(2-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide722 429 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(4-nitro-phenyl)-ethyl]-thioureido}-phenyl)-amide 723 399[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(1-methyl-2-phenyl-ethyl)-thioureido]-phenyl}-amide 724 437N-{4-[3-(4-tert-Butyl-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide 725409 N-{4-[3-(3,5-Dimethyl-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide726 400 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(2-hydroxy-1-phenyl-ethyl)-thioureido]-phenyl}-amide 727 4092-Fluoro-N-{4-[3-(1-methyl-1-phenyl-ethyl)-thioureido]-phenyl}-benzamide728 399 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(1-methyl-1-phenyl-ethyl)-thioureido]-phenyl}-amide 729 405[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(2-chloro-benzyl)-thioureido]-phenyl}-amide 730 388[1,2,3]Thiadiazole-4-carboxylic acid(4-[3-(2-fluoro-benzyl)-thioureido]-phenyl}-amide 731 438[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-trifluoromethyl-benzyl)-thioureido]-phenyl}-amide 732 388[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-fluoro-benzyl)-thioureido]-phenyl}-amide 733 435[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(2-chloro-phenoxy)-ethyl]-thioureido}-phenyl)-amide 734 479[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3-bromo-phenoxy)-ethyl]-thioureido}-phenyl)-amide 735 418[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(2-fluoro-phenoxy)-ethyl]-thioureido}-phenyl)-amide 736 418[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3-fluoro-phenoxy)-ethyl]-thioureido}-phenyl)-amide 737 486[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(2-fluoro-5-trifluoromethyl-phenoxy)-ethyl]-thioureido}-phenyl)-amide738 384 Furan-2-carboxylic acid(4-{3-[2-(2-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 739 435[1,2,,3]Thiadiazole-4-carboxylic acid{4-[3-(4-bromo-phenyl)-thioureido]-phenyl}-amide 740 374[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-fluoro-phenyl)-thioureido]-phenyl}-amide 741 388[1,2,3)Thiadiazole-4-carboxylic acid{4-[3-(4-fluoro-benzyl)-thioureido]-phenyl}-amide 742 405[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-chloro-benzyl)-thioureido]-phenyl}-amide 743 449[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-bromo-benzyl)-thioureido]-phenyl}-amide 744 332N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-acetamide 745438 Thiazole-4-carboxylic acid{4-[3-(3,4-dichloro-benzyl)-thioureido]-phenyl}-amide 746 455Thiazole-4-carboxylic acid{4-[3-(2-fluoro-5-trifluoromethyl-benzyl)-thioureido]-phenyl}-amide 747426 Thiazole-4-carboxylic acid{4-[3-(4-tert-butyl-benzyl)-thioureido]-phenyl}-amide 748 374[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(2-fluoro-phenyl)-thioureido]-phenyl}-amide 749 374[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-fluoro-phenyl)-thioureido]-phenyl}-amide 750 526[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3-iodo-phenoxy)-ethyl]-thioureido}-phenyl)-amide 751 409N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-phenyl-acetamide752 425N-(4-{3-[1-(4-Fluoro-phenyl)-ethy1]-thioureido}-phenyl)-2-methoxy-benzamide753 425N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-3-methoxy-benzamide754 425N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-4-methoxy-benzamide755 4292-Chloro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide756 4294-Chloro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide757 453 Acetic acid4-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenylcarbamoyl)-phenylester 758 394N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide 759395N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-isonicotinamide760 410N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-4-hydroxy-benzamide761 4293-Chloro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide762 470 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3-fluoro-5-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide763 520 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(2,4-bis-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide764 470 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(4-fluoro-3-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide765 4384-Dimethylamino-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide766 470 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(2-fluoro-3-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide767 470 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(2-fluoro-5-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide768 510 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3-iodo-phenyl)-ethyl]-thioureido}-phenyl)-amide 769 470[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(4-fluoro-2-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide770 463 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3-bromo-phenyl)-ethyl]-thioureido}-phenyl)-amide 771 4272-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-propyl]-thioureido}-phenyl)-benzamide772 4752-Fluoro-N-(4-{3-[(4-fluoro-phenyl)-phenyl-methyl]-thioureido}-phenyl)-benzamide773 4552-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-pentyl]-thioureido}-phenyl)-benzamide774 4892-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-2-phenyl-ethyl]-thioureido}-phenyl)benzamide775 409 2-Fluoro-N-{4-[3-(1-o-tolyl-ethyl)-thioureido]-phenyl}-benzamide776 409 2-Fluoro-N-{4-[3-(1-m-tolyl-ethyl)-thioureido]-phenyl}-benzamide777 4252-Fluoro-N-(4-{3-[1-(4-methoxy-phenyl)-ethyl]-thioureido}-phenyl)-benzamide778 4122-Fluoro-N-(4-{3-[1-(2-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide779 429N-(4-{3-[1-(3-Chloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide780 473N-(4-{3-[1-(3-Bromo-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide781 429N-(4-{3-[1-(4-Chloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide782 409 2-Fluoro-N-{4-[3-(1-p-tolyl-ethyl)-thioureido]-phenyl}-benzamide783 473N-(4-{3-[1-(2-Bromo-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide784 429N-(4-{3-[1-(2-Chloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide785 4622-Fluoro-N-(4-{3-[1-(2-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-benzamide786 4622-Fluoro-N-(4-{3-[1-(3-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-benzamide787 4622-Fluoro-N-(4-{3-[1-(4-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-benzamide788 4252-Fluoro-N-(4-{3-[1-(2-methoxy-phenyl)-ethyl]-thioureido}-phenyl)-benzamide789 4252-Fluoro-N-(4-{3-[1-(3-methoxy-phenyl)-ethyl]-thioureido}-phenyl)-benzamide790 4412-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-2-methyl-propyl]-thioureido}-phenyl)-benzamide791 419N-(4-{3-[1-(3-Cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide792 419N-(4-{3-[1-(4-Cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide793 438N-(4-{3-[1-(4-Dimethylamino-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide794 438N-(4-{3-[1-(3-Dimethylamino-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide795 4732-Bromo-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide796 446 Quinoline-2-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 797 4102-Fluoro-N-{4-[3-(2-hydroxy-1-phenyl-ethyl)-thioureido]-phenyl}-benzamide798 332 2-Fluoro-N-[4-(3-isopropyl-thioureido)-phenyl]-benzamide 799 4452-Fluoro-N-{4-(3-(1-naphthalen-2-yl-ethyl)-thioureido]-phenyl}-benzamide800 4123-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide801 4124-Fluoro-N-(4-{3-(1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide802 3842-Fluoro-N-{4-[3-(1-furan-2-yl-ethyl)-thioureido]-phenyl}-benzamide 8033952-Fluoro-N-{4-(3-(1-pyridin-4-yl-ethyl)-thioureido]-phenyl}-benzamide804 3972-Fluoro-N-(4-{3-[1-(1-methyl-1H-pyrrol-2-yl)-ethyl)-thioureido}-phenyl)-benzamide805 4012-Fluoro-N-{4-[3-(1-thiophen-3-yl-ethyl)-thioureido]-phenyl}-benzamide806 445N-{4-[3-(3-Chloro-4-ethoxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide807 459N-{4-[3-(3-Chloro-4-propoxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide808 459N-{4-(3-(3-Chloro-4-isopropoxy-phenyl)-thioureido-phenyl}-2-fluoro-benzamide809 473N-{4-[3-(4-Butoxy-3-chloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide810 5222-Fluoro-N-{4-[3-(3-iodo-4-methoxy-phenyl)-thioureido]-phenyl}-benzamide811 475N-{4-[3-(3-Bromo-4-methoxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide812 520N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl)-thioureido}-phenyl)-2-iodo-benzamide813 346N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-propionamide 814286 N-[4-(3-Phenyl-thioureido)-phenyl]-acetamide

EXAMPLE 815 (Method 32) 2,3]Thiadiazole-4-carboxylic Acid{4-[3-(2,5-dichloro-phenyl-thioureido]-phenyl}-amide

To a solution of 2,5-dichloroaniline (0.16 g) in tetrahydrofuran (20 mL)is added freshly prepared 1,1′-thiocarbonyldiimidazole (0.20 g) and themixture is stirred for approximately 30 minutes at room temperature.[1,2,3]-Thiadiazole-4-carboxylic acid (4-amino-phenyl) amide (0.22 g) isadded to the reaction flask and the mixture is stirred for approximately6 hours. The solvent is then removed by evaporation under reducedpressure and warm acetonitrile (3 mL) is added. After 15 hours themixture is filtered and the collected precipitate is washed withacetonitrile then diethyl ether, and air dried to provide the desiredproduct as a white powder.

Used the above procedure and appropriate starting materials thefollowing compounds were prepared:

EX. NO. M + H COMPOUND NAME 816 321N-{4-[3-(3-Chloro-phenyl)-thioureido]-phenyl}-acetamide 817 413N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-benzamide 818443N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-2-methoxy-benzamide819 443N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-3-methoxy-benzamide820 443N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-4-methoxy-benzamide821 431N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-4-methoxy-benzamide822 431N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-3-fluoro-benzamide823 431N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-4-fluoro-benzamide824 437 Furan-2-carboxylic acid{4-[3-(3,5-dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-amide 825 511{4-[3-(5-Bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-carbamic acidhexyl ester 826 481 Hexanoic acid{4-[3-(5-bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 827 505N-{4-[3-(5-Bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide828 477 Furan-2-carboxylic acid{4-[3-(5-bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 829 501N-{4-[3-(5-Bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-methyl-benzamide830 517N-{4-[3-(5-Bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-4-methoxy-benzamide831 395N-{4-[3-(5-Chloro-2-ethoxy-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide832 395N-{4-[3-(5-Chloro-4-ethoxy-2-methoxy-phenyl)-thioureido]-phenyl}-acetamide833 423N-{4-[3-(2-Butoxy-5-chloro-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide834 423N-{4-[3-(4-Butoxy-5-chloro-2-methoxy-phenyl)-thioureido]-phenyl}-acetamide835 457N-{4-[3-(2-Benzyloxy-5-chloro-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide836 457N-{4-[3-(4-Benzyloxy-5-chloro-2-methoxy-phenyl)-thioureido]-phenyl}-acetamide837 421 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-chloro-4-methoxy-phenyl)-thioureido]-phenyl}-amide 838 4242-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-5-methoxy-phenoxy}-acetamide839 367N-{4-[3-(5-Chloro-2-hydroxy-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide840 367N-{4-[3-(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]-phenyl}-acetamide841 447N-[4-(3-{3-Chloro-4-[methyl-(1-methyl-piperidin-4-yl)-amino]-phenyl}-thioureido)-phenyl]-acetamide842 426N-(4-{3-[3-Chloro-4-(methyl-phenyl-amino)-phenyl]-thioureido}-phenyl)-acetamide843 509N-[4-(3-{4-[(1-Benzyl-pyrrolidin-3-yl)-methyl-amino]-3-chloro-phenyl}-thioureido)-phenyl]-acetamide844 418N-(4-{3-[3-Chloro-4-(cyclopentyl-methyl-amino)-phenyl]-thioureido}-phenyl)-acetamide845 433N-[4-(3-{3-Chloro-4-[methyl-(1-methyl-pyrrolidin-3-yl)-amino]-phenyl}-thioureido)-phenyl]-acetamide846 419 Furan-2-carboxylic acid{4-[3-(3-chloro-4-methylsulfanyl-phenyl)-thioureido]-phenyl}-amide 847447N-{4-[3-(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide848 465N-{4-[3-(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]-phenyl}-2,6-difluoro-benzamide849 445N-{4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide850 441N-{4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-2-methyl-benzamide851 434 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-chloro-4-dimethylamino-phenyl)-thioureido]-phenyl}-amide 852444N-{4-[3-(3-Chloro-4-dimethylamino-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide853 517 [1,2,3]Thiadiazole-4-carboxylic acid[4-(3-{3-chloro-4-[methyl-(1-methyl-piperidin-4-yl)-amino]-phenyl}-thioureido)-phenyl]-amide854 579 [1,2,3]Thiadiazole-4-carboxylic acid[4-(3-{4-[(1-benzyl-pyrrolidin-3-yl)-methyl-amino]-3-chloro-phenyl}-thioureido)-phenyl]-amide855 527N-[4-(3-{3-Chloro-4-[methyl-(1-methyl-piperidin-4-yl)-amino]-phenyl}-thioureido)-phenyl]-2-fluoro-benzamide856 435 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(5-chloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-amide 857589N-[4-(3-{4-[(1-Benzyl-pyrrolidin-3-yl)-methyl-amino]-3-chloro-phenyl}-thioureido)-phenyl]-2-fluoro-benzamide858 501 Furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-3-trifluoromethyl-phenyl}-amide859 366 2-Fluoro-N-[4-(3-phenyl-thioureido)-phenyl]-benzamide 860 338Furan-2-carboxylic acid [4-(3-phenyl-thioureido)-phenyl]-amide 861 356[1,2,3]Thiadiazole-4-carboxylic acid[4-(3-phenyl-thioureido)-phenyl]-amide 862 365N-(4-{3-[3-Chloro-4-(1-hydroxy-ethyl)-phenyl]-thioureido}-phenyl)-acetamide863 435 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[3-chloro-4-(1-hydroxy-ethyl)-phenyl]-thioureido}-phenyl)-amide864 365N-(4-{3-[3-Chloro-4-(2-hydroxy-ethyl)-phenyl]-thioureido}-phenyl)-acetamide865 445N-(4-{3-[3-Chloro-4-(1-hydroxy-ethyl)-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide866 417 Furan-2-carboxylic acid(4-{3-[3-chloro-4-(1-hydroxy-ethyl)-phenyl]-thioureido}-phenyl)-amide867 371 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-amino-phenyl)-thioureido]-phenyl}-amide 868 501Furan-2-carboxylic acid{4-[3-(3-bromo-4-trifluoromethoxy-phenyl)-thioureido]-phenyl}-amide 869423 N-{4-[3-(3-tert-Butyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide870 440 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-chloro-3,5-dichloro-phenyl)-thioureido]-phenyl}-amide 974 485N-{4-[3-(1-Benzofuran-2-yl-ethyl)-thioureido]-phenyl}-2-trifluoromethyl-benzamide975 412N-(4-Fluoro-phenyl)4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-benzamide976 446 Isoquinoline-1-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 977 468Isoquinoline-1-carboxylic acid{4-[3-(1-benzofuran-2-yl-ethyl)-thioureido-phenyl}-amide 978 506Isoquinoline-1-carboxylic acid(4-{3-[1-(4-bromo-phenyl)-ethyl]-thioureido}-phenyl)-amide 979 453Isoquinoline-1-carboxylic acid(4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureido}-phenyl)-amide 980 435Benzofuran-2-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 981 457Benzofuran-2-carboxylic acid{4-[3-(1-benzofuran-2-yl-ethyl)-thioureido]-phenyl}-amide 982 495Benzofuran-2-carboxylic acid(4-{3-[1-(4-bromo-phenyl)-ethyl]-thioureido}-phenyl)-amide 983 442Benzofuran-2-carboxylic acid(4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureido}-phenyl)-amide 984 446Isoquinoline-3-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 985 468Isoquinoline-3-carboxylic acid{4-[3-(1-benzofuran-2-yl-ethyl)-thioureido]-phenyl}-amide 986 453Isoquinoline-3-carboxylic acid(4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureido}-phenyl)-amide 987 506Isoquinoline-3-carboxylic acid(4-{3-[1-(4-bromo-phenyl)-ethyl]-thioureido}-phenyl)-amide 988 446Quinoline-3-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 989 446Quinoline-4-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 990 446Quinoline-6-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 991 446Quinoline-8-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 992 462N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-trifluoromethyl-benzamide993 4192-Cyano-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide994 473N-{4-[3-(3-Chloro-4-isobutoxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide995 4142-Fluoro-N-{4-[3-(3-fluoro-4-methoxy-phenyl)-thioureido]-phenyl}-benzamide996 475N-(4-{3-[3-Chloro-4-(2-methoxy-ethoxy)-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide997 3982-Fluoro-N-{4-[3-(3-fluoro-4-methyl-phenyl)-thioureido]-phenyl}-benzamide998 4642-Fluoro-N-{4-[3-(4-methoxy-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-benzamide999 449N-{4-[3-(2-Amino-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide1000 459N-(4-{3-[1-(3-Chloro-4-methoxy-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide1001 417N-{4-[3-(5-Chloro-2-hydroxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide1002 435N-{4-[3-(1-Benzofuran-2-yl-ethyl)-thioureido]-phenyl}-2-fluoro-benzamide1003 4482-Fluoro-N-{4-[3-(4-methyl-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-benzamide1004 473(S)-N-(4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide1005 473N-(4-{3-[(1R)-1-(4-Bromo-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide1006 4942-Fluoro-N-(4-{3-[2-methoxy-4-(2,2,2-trifluoro-ethoxy)-phenyl]-thioureido}-phenyl)-benzamide1007 399N-{4-[3-(2-Amino-5-fluoro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide1008 502N-(4-{3-[1-(4-Dimethylsulfamoyl-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide1009 5422-Fluoro-N-[4-(3-{1-[4-(piperidine-1-sulfonyl)-phenyl]-ethyl}-thioureido)-phenyl]-benzamide1010 562N-(4-{3-[2,4-Bis-(2,2,2-trifluoro-ethoxy)-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide1011 4092-Fluoro-N-{4-[3-((1S)-1-p-tolyl-ethyl)-thioureido]-phenyl}-benzamide1012 4092-Fluoro-N-{4-[3-((1R)-1-p-tolyl-ethyl)-thioureido]-phenyl}-benzamide1013 3942-Fluoro-N-{4-[3-((1S)-1-phenyl-ethyl)-thioureido]-phenyl}-benzamide1014 429N-(4-{3-[(1R)-1-(4-Chloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide1015 429N-(4-{3-[(1S)-1-(4-Chloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide1016 3942-Fluoro-N-{4-[3-((1R)-1-phenyl-ethyl)-thioureido]-phenyl}-benzamide1017 432N-(4-{3-[1-(4-Cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-methoxy-benzamide1018 447N-{4-[3-(1-Benzofuran-2-yl-ethyl)-thioureido]-phenyl}-2-methoxy-benzamide1019 485N-(4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-phenyl)-2-methoxy-benzamide1020 4193-Cyano-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide1021 462N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-4-trifluoromethyl-benzamide1022 4194-Cyano-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide1023 4692-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2,3,5,6-tetramethyl-phenyl)-benzamide1024 480N-(4-{3-[1-(4-Cyano-phenyl)-ethyl]-thioureido]-2,5-dimethoxy-phenyl}-2-fluoro-benzamide1025 4732-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2,5-dimethoxy-phenyl)-benzamide1026 530N-{3,5-Dichloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide1027 447N-(3-Chloro-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide1028 4802,3,4,5-Tetrafluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-3-methyl-phenyl)-benzamide1029 4622,4,5-Trifluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-3-methyl-phenyl)-benzamide1030 4272-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-3-methyl-phenyl)-benzamide1031 4572-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2-methoxy-5-methyl-phenyl)-benzamide1032 4432-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-3-methoxy-phenyl)-benzamide1033 570N-(2,6-Dibromo-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide1034 4802-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2-trifluoromethyl-phenyl)-benzamide1035 541N-(4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-2-trifluoromethyl-phenyl)-2-fluoro-benzamide1036 487N-(4-{3-[1-(4-Cyano-phenyl)-ethyl]-thioureido}-2-trifluoromethyl-phenyl)-2-fluoro-benzamide1037 503N-{4-[3-(1-Benzofuran-2-yl-ethyl)-thioureido]-2-trifluoromethyl-phenyl}-2-fluoro-benzamide1038 447N-(2-Chloro-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide1039 454N-(2-Chloro-4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide1040 437N-(2-Cyano-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide1041 498N-(4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-2-cyano-phenyl)-2-fluoro-benzamide1042 445N-(2-Cyano-4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide1043 460N-{4-[3-(1-Benzofuran-2-yl-ethyl)-thioureido]-2-cyano-phenyl}-2-fluoro-benzamide1044 517N-(2-Benzoyl-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide1045 4272-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2-methyl-phenyl)-benzamide1046 487N-(4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-2-methyl-phenyl)-2-fluoro-benzamide1047 434N-(4-{3-[1-(4-Cyano-phenyl)-ethyl]-thioureido}-2-methyl-phenyl)-2-fluoro-benzamide1048 449N-{4-[3-(1-Benzofuran-2-yl-ethyl)-thioureido]-2-methyl-phenyl}-2-fluoro-benzamide1049 456N-(2-Dimethylamino-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide1050 526N-(2-Benzyloxy-4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide1051 519N-(2-Benzyloxy-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide1052 603N-[4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-2-(2-morpholin-4-yl-ethoxy)-phenyl]-2-fluoro-benzamide1053 603N-[4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-2-(2-morpholin-4-yl-ethoxy)-phenyl]-2-fluoro-benzamide1054 5422-Fluoro-N-[4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2-(2-morpholin-4-yl-ethoxy)-phenyl]-benzamide1055 485N-(2-Butoxy-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide1056 492N-(2-Butoxy-4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide1057 589N-[4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-2-(2-diethylamino-ethoxy)-phenyl]-2-fluoro-benzamide1058 528N-(2-(2-Diethylamino-ethoxy)-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide1059 589N-[4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-2-(2-diethylamino-ethoxy)-phenyl]-2-fluoro-benzamide1060 457N-(2-Ethoxy-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide1061 464N-(4-{3-[1-(4-Cyano-phenyl)-ethyl]-thioureido}-2-ethoxy-phenyl)-2-fluoro-benzamide1062 4682-Fluoro-N-[4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2-(2-nitrilo-ethoxy)-phenyl]-benzamide1063 475N-[4-{3-[1-(4-Cyano-phenyl)-ethyl]-thioureido}-2-(2-nitrilo-ethoxy)-phenyl]-2-fluoro-benzamide1064 4432-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2-methoxy-phenyl)-benzamide1065 4892-Fluoro-N-(5-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-biphenyl-2-yl)-benzamide1066 514 Isoquinoline-1-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2-trifluoromethyl-phenyl)-amide1067 503 Benzofuran-2-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2-trifluoromethyl-phenyl)-amide1068 514 Isoquinoline-3-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2-trifluoromethyl-phenyl)-amide1069 471 Isoquinoline-1-carboxylic acid(2-cyano-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 1070460 Benzofuran-2-carboxylic acid(2-cyano-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 1071471 Isoquinoline-3-carboxylic acid(2-cyano-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 1072460 Isoquinoline-1-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2-methyl-phenyl)-amide1073 449 Benzofuran-2-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2-methyl-phenyl)-amide1074 460 Isoquinoline-3-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2-methyl-phenyl)-amide1075 396 Pyrazine-2-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 1076 401Thiophene-2-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 1077 401Thiophene-3-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 1078 5002-Isopropyl-thiazole-4-carboxylic acid{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 1079466 2-Isopropyl-thiazole-4-carboxylic acid{4-[3-(3,5-dichloro-phenyl)-thioureido]-phenyl}-amide 1080 4662-Isopropyl-thiazole-4-carboxylic acid{4-[3-(3,4-dichloro-phenyl)-thioureido]-phenyl}-amide 1081 5342-Isopropyl-thiazole-4-carboxylic acid{4-[3-(3,5-bis-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 1082480 2-Butyl-thiazole-4-carboxylic acid{4-[3-(3,4-dichloro-phenyl)-thioureido]-phenyl}-amide 1083 5142-Butyl-thiazole-4-carboxylic acid{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 1084480 2-Butyl-thiazole-4-carboxylic acid{4-[3-(3,5-dichloro-phenyl)-thioureido]-phenyl}-amide 1085 5482-Butyl-thiazole-4-carboxylic acid{4-[3-(3,5-bis-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 1086438 2-Methyl-thiazole-4-carboxylic acid{4-[3-(3,5-dichloro-phenyl)-thioureido]-phenyl}-amide 1087 4382-Methyl-thiazole-4-carboxylic acid{4-[3-(3,4-dichloro-phenyl)-thioureido]-phenyl}-amide 1088 5052-Methyl-thiazole-4-carboxylic acid{4-[3-(3,5-bis-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 1089534 2-Phenyl-thiazole-4-carboxylic acid{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 1090500 2-Phenyl-thiazole-4-carboxylic acid{4-[3-(3,5-dichloro-phenyl)-thioureido]-phenyl}-amide 1091 5002-Phenyl-thiazole-4-carboxylic acid{4-[3-(3,4-dichloro-phenyl)-thioureido]-phenyl}-amide 1092 5682-Phenyl-thiazole-4-carboxylic acid{4-[3-(3,5-bis-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide. 10934012-Fluoro-N-{4-[3-(1-thiazol-2-yl-ethyl)-thioureido]-phenyl}-benzamide1094 5882-Fluoro-N-[4-(3-{1-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-ethyl}-thioureido)-phenyl]-benzamide1095 4462-Fluoro-N-{4-[3-(1-quinolin-2-yl-ethyl)-thioureido]-phenyl}-benzamide1096 4462-Fluoro-N-{4-[3-(1-quinolin-4-yl-ethyl)-thioureido]-phenyl}-benzamide1097 4462-Fluoro-N-{4-[3-(1-isoquinolin-3-yl-ethyl)-thioureido]-phenyl}-benzamide1098 4462-Fluoro-N-{4-[3-(1-isoquinolin-1-yl-ethyl)-thioureido]-phenyl}-benzamide1099 4462-Fluoro-N-{4-[3-(1-quinolin-6-yl-ethyl)-thioureido]-phenyl}-benzamide1100 4462-Fluoro-N-{4-[3-(1-quinolin-3-yl-ethyl)-thioureido]-phenyl}-benzamide1101 4132-Methoxy-N-{4-[3-(1-thiophen-3-yl-ethyl)-thioureido]-phenyl}-benzamide

EXAMPLE 871 (Method 33) [1,2,3]Thiadiazole-4-carboxylic Acid{4-[3-(3,5-dichloro-phenyl)-thioureido]-phenyl}-amide

To a solution of 3,5-dichloroaniline (0.16 g) in tetrahydrofuran (20 mL)is added freshly prepared 1,1′-thiocarbonyl-di-(1,2,4)-triazole (0.20 g)and the mixture is stirred for approximately 30 minutes at roomtemperature. [1,2,3]-Thiadiazole-4-carboxylic acid (4-amino-phenyl)amide (0.22 g) is added to the reaction flask and the mixture is stirredfor approximately 6 hours. The solvent is then removed by evaporationunder reduced pressure and warm acetonitrile (3 mL) is added. After 15hours the mixture is filtered and the collected precipitate is washedwith acetonitrile then diethyl ether, and air dried to provide thedesired product as a white powder. [M+H]424.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

EX. NO. M + H COMPOUND NAME 872 465N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-3-fluoro-benzamide873 477N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-2-methoxy-benzamide874 465N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido)-phenyl}-2-fluoro-benzamide875 477N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-3-methoxy-benzamide876 399N-{4-[3-(3,5-Dichloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-acetamide877 365N-{4-[3-(3-Chloro-4-methoxy-5-methyl-phenyl)-thioureido]-phenyl}-acetamide878 331 N-{4-[3-(2-Nitro-phenyl)-thioureido]-phenyl}-acetamide 879 331N-{4-[3-(4-Nitro-phenyl)-thioureido]-phenyl}-acetamide 880 477N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-4-methoxy-benzamide881 351N-{4-[3-(2-Chloro-5-methoxy-phenyl)-thioureido]-phenyl}-acetamide 8824282-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-acetamide883 443{4-[3-(4-Acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-aceticacid methyl ester 884 457{4-[3-(4-Acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-aceticacid ethyl ester 885 447N-{4-[3-(3,5-Dichloro-4-phenoxy-phenyl)-thioureido]-phenyl}-acetamide886 410N-(4-{3-[3,5-Dichloro-4-(2-nitrilo-ethoxy)-phenyl]-thioureido}-phenyl)-acetamide887 485{4-[3-(4-Acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-aceticacid tert-butyl ester 888 469 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,5-dichloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-amide889 335 N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]-phenyl}-acetamide890 335 N-{4-[3-(5-Chloro-2-methyl-phenyl)-thioureido]-phenyl}-acetamide891 703N{4-[3-(4-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyldisulfanyl}-3-chloro-phenyl)-thioureido]-phenyl}-acetamide892 369N-{4-[3-(3,5-Dichloro-4-methyl-phenyl)-thioureido]-phenyl}-acetamide 893598N-{4-[3-(3,5-Diiodo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide894 504N-{4-[3-(3,5-Dibromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide895 317 N-{4-[3-(6-Methoxy-pyridin-3-yl)-thioureido]-phenyl}-acetamide896 347N-{4-[3-(2,6-Dimethoxy-pyridin-3-yl)-thioureido]-phenyl}-acetamide 897457 Acetic acid2-{4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-ethylester 898 365 4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-benzoicacid 899 346N-{4-[3-(3-Chloro-4-cyano-phenyl)-thioureido]-phenyl}-acetamide 900 512N-(4-{3-[5-Chloro-2-(4-chloro-phenoxy)-4-pyrrol-1-yl-phenyl]-thioureido}-phenyl)-acetamide901 355 N-{4-[3-(3,4-Dichloro-phenyl)-thioureido]-phenyl}-acetamide 902339 N-{4-[3-(3-Chloro-4-fluoro-phenyl)-thioureido]-phenyl}-acetamide 903447 N-{4-[3-(3-Chloro-4-iodo-phenyl)-thioureido]-phenyl}-acetamide 904400 N-{4-[3-(4-Bromo-3-chloro-phenyl)-thioureido]-phenyl}-acetamide 905424N-[4-(3-{4-[Bis-(2-hydroxy-ethyl)-amino]-3-chloro-phenyl}-thioureido)-phenyl]-acetamide906 434N-(4-{3-[3-Chloro-4-(hexyl-methyl-amino)-phenyl]-thioureido}-phenyl)-acetamide907 406N-(4-{3-[3-Chloro-4-(isobutyl-methyl-amino)-phenyl]-thioureido}-phenyl)-acetamide908 389N-{4-[3-(3-Chloro-4-trifluoromethyl-phenyl)-thioureido]-phenyl}-acetamide909 441 Furan-2-carboxylic acid{4-[3-(3-chloro-4-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 910459 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-chloro-4-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 911469N-{4-[3-(3-Chloro-4-trifluoromethyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide912 435N-{4-[3-(3,4-Dichloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 913407 Furan-2-carboxylic acid{4-[3-(3,4-dichloro-phenyl)-thioureido]-phenyl}-amide 914 425[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,4-dichloro-phenyl)-thioureido]-phenyl}-amide 915 480N-{4-[3-(4-Bromo-3-chloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide916 527N-{4-[3-(3-Chloro-4-iodo-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide917 452 Furan-2-carboxylic acid{4-[3-(4-bromo-3-chloro-phenyl)-thioureido]-phenyl}-amide 918 499Furan-2-carboxylic acid{4-[3-(3-chloro-4-iodo-phenyl)-thioureido]-phenyl}-amide 919 391Furan-2-carboxylic acid{4-[3-(3-chloro-4-fluoro-phenyl)-thioureido]-phenyl}-amide 920 470[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-bromo-3-chloro-phenyl)-thioureido]-phenyl}-amide 921 517[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-chloro-4-iodo-phenyl)-thioureido]-phenyl}-amide 922 419N-{4-[3-(3-Chloro-4-fluoro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide923 409 [1,2,3]Thiadiazole-4-carboxylicacid{4-[3-(3-chloro4-fluoro-phenyl)-thioureido]-phenyl}-amide 924 388N-{4-[3-(3-Chloro-4-isoxazol-5-yl-phenyl)-thioureido]-phenyl}-acetamide925 387N-(4-{3-[3-Chloro-4-(1H-pyrazol-3-yl)-phenyl]-thioureido}-phenyl)-acetamide926 355 N-{4-[3-(2,3-Dichloro-phenyl)-thioureido]-phenyl}-acetamide 927435 N-{4-[3-(2,3-Dichloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide928 407 Furan-2-carboxylic acid{4-[3-(2,3-dichloro-phenyl)-thioureido]-phenyl}-amide 929 425[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(2,3-dichloro-phenyl)-thioureido]-phenyl}-amide 930 355N-{4-[3-(2,5-Dichloro-phenyl)-thioureido]-phenyl}-acetamide 931 435N-{4-[3-(2,5-Dichloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 932407 Furan-2-carboxylic acid{4-[3-(2,5-dichloro-phenyl)-thioureido]-phenyl}-amide 933 355N-{4-[3-(3,5-Dichloro-phenyl)-thioureido]-phenyl}-acetamide 934 435N-{4-[3-(3,5-Dichloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 935407 Furan-2-carboxylic acid{4-[3-(3,5-dichloro-phenyl)-thioureido]-phenyl}-amide 936 390N-{4-[3-(3,4,5-Trichloro-phenyl)-thioureido]-phenyl}-acetamide 937 4702-Fluoro-N-{4-[3-(3,4,5-trichloro-phenyl)-thioureido]-phenyl}-benzamide938 442 Furan-2-carboxylic acid{4-[3-(3,4,5-trichloro-phenyl)-thioureido]-phenyl}-amide 939 460[1,2,3]Thiadiazole-4-carboxylicacid{4-[3-(3,4,5-trichloro-phenyl)-thioureido]-phenyl}-amide 940 458[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-chloro-4-isoxazol-5-yl-phenyl)-thioureido]-phenyl}-amide 941457 [1,2,3]Thiadiazole-4-carboxylicacid(4-{3-[3-chloro-4-(1H-pyrazol-3-yl)-phenyl]-thioureido}-phenyl)-amide942 391 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-chloro-phenyl)-thioureido]-phenyl}-amide 943 373Furan-2-carboxylic acid{4-[3-(3-chloro-phenyl)-thioureido]-phenyl}-amide 944 401N-{4-[3-(3-Chloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 945 373Furan-2-carboxylic acid{4-[3-(4-chloro-phenyl)-thioureido]-phenyl}-amide 946 401N-{4-[3-(4-Chloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 947 391[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-chloro-phenyl)-thioureido]-phenyl}-amide 948 401N-{4-[3-(2-Chloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 949 3963-(3-{4-[(Furan-2-carbonyl)-amino]-phenyl}-thioureido)-benzoic acidmethyl ester 950 4243-{3-[4-(2-Fluoro-benzoylamino)-phenyl]-thioureido}-benzoic acid methylester 951 4143-(3-{4-[([1,2,3]Thiadiazole-4-carbonyl)-amino]-phenyl}-thioureido)-benzoicacid methyl ester 952 409N-[4-[[[[3-(Aminocarbonyl)phenyl]amino]thioxomethyl]amino]phenyl]-2-fluoro-benzamide953 373 Furan-2-carboxylic acid{4-[3-(2-chloro-phenyl)-thioureido]-phenyl}-amide 954 381Furan-2-carboxylic acid{4-[3-(3-carbamoyl-phenyl)-thioureido]-phenyl}-amide 955 399[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-carbamoyl-phenyl)-thioureido]-phenyl}-amide 956 391[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(2-chloro-phenyl)-thioureido]-phenyl}-amide 957 356Furan-2-carboxylic acid{4-[3-(3-fluoro-phenyl)-thioureido]-phenyl}-amide 958 383Furan-2-carboxylic acid {4-[3-(3-nitro-phenyl)-thioureido]-phenyl}-amide959 411 2-Fluoro-N-{4-[3-(3-nitro-phenyl)-thioureido]-phenyl}-benzamide960 422 Furan-2-carboxylic acid{4-[3-(3-trifluoromethoxy-phenyl)-thioureido]-phenyl}-amide 961 4502-Fluoro-N-{4-[3-(3-trifluoromethoxy-phenyl)-thioureido]-phenyl}-benzamide962 384 2-Fluoro-N-{4-[3-(3-fluoro-phenyl)-thioureido]-phenyl}-benzamide963 410 3-{3-[4-(2-Fluoro-benzoylamino)-phenyl]-thioureido}-benzoic acid964 382 3-(3-{4-[(Furan-2-carbonyl)-amino]-phenyl}-thioureido)-benzoicacid 965 408N-{4-[3-(3-Acetyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 966 502N-{4-[3-(3-Butylsulfamoyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide967 380 Furan-2-carboxylic acid{4-[3-(3-acetyl-phenyl)-thioureido]-phenyl}-amide 968 447Furan-2-carboxylic acid(4-{3-[3-(2-hydroxy-ethanesulfonyl)-phenyl]-thioureido}-phenyl)-amide969 4752-Fluoro-N-(4-{3-[3-(2-hydroxy-ethanesulfonyl)-phenyl]-thioureido}-phenyl)-benzamide970 474 Furan-2-carboxylic acid{4-[3-(3-butylsulfamoyl-phenyl)-thioureido]-phenyl}-amide

EXAMPLE 971 (Method 57) 1-(4-Fluoro-phenyl)-2-methyl-propan-1-ol

To solution of 4-fluorobenzaldehyde (2.0 g) in diethyl ether (40 mL) at0° C. is added dropwise isopropylmagesium bromide (2.0 M, 9.6 mL) withstirring. After 1.5 hours the reaction is quenched with aqueous ammoniumchloride and extracted with diethyl ether. The diethyl ether extractsare washed with saturated sodium chloride, dried over anhydrousmagnesium sulfate, flitered and evaporated to give an oil. The oil ispurifed by silica gel chromatography eluting with 10%dichloromethane-hexanes to give the product, a yellow oil (1.76 g).

EXAMPLE 972 (Method 58) 1-(4-Fluoro-phenyl)-2-methyl-propan-1-one

To a solution of 1-(4-Fluoro-phenyl)-2-methyl-propan-1-ol (1.6 g) inacetone (10 mL) at 0° C. is added Jones reagent (20 mL) with stirring.After 10 minutes excess Jones reagent is destroyed by addition ofisopropyl alcohol. Diethyl ether is added followed by anhydrousmagnesium and the mixture is filtered and evaporated to give theproduct, a yellow oil (1.2 g).

EXAMPLE 973 (Method 59) 3-Dimethylamino-5-trifluoromethyl-benzonitrile

To a solution of 3-dimethylamino-5-trifluoromethylbromobenzene (7.3 g)in N,N-dimethylformamide (20 mL) is added cuprous cyanide (2.7 g) andthe reaction heated at reflux for 12 hours. The reaction is diluted withwater (40 mL) and dichloromethane is added. The dichloromethane fractionis washed with concentrated ammonium hydroxide, then water. The solutionis dried over anhydrous magnesium sulfate, filtered and concentrated togive a yellow solid which is recrystallized from hexanes to give ayellow solid, (4.7 g).

The foregoing compounds were tested for activity as herpes virusinhibitors using the following assays.

HUMAN CYTOMEGALOVIRUS

Yield assay. Monolayer cultures of human foreskin fibroblasts areinfected with HCMV wild-type, typically at a multiplicity of infectionequal to 0.2, in the presence of inhibitor compound (varyingconcentrations). At three days post-infection, total virus produced inthese cultures (i.e. virus yield) is assessed by harvesting and titeringthe virus in 12-well plates of cultured human foreskin fibroblasts (donein the absence of inhibitor). Plaques are quantified at 2 weekspost-infection. An inhibitor of HCMV is identified by the reduction intiter of virus yield in the presence, compared to the titer in theabsence of compound. In this assay, the relative anti-HCMV activity ofan inhibitor is typically determined by calculating the IC₅₀ or IC₉₀value, that is, the amount of compound required to reduce the virusyield by 50% or 90%, respectively. Table I describes IC₅₀ data forcompounds tested against HCMV.

Microtiter plate assay. Ninety-six well plate cultures of human foreskinfibroblasts are infected in the presence of inhibitor compound with aHCMV recombinant mutant virus whose genome contains the prokaryoticbeta-glucuronidase gene (Jefferson, R. A., S. M. Burgess, and D. Hirsh.1986. Beta-glucuronidase from Escherichia coli as a gene fusion marker.Proc. Natl. Acad. Sci. USA 83:8447-8451) whose expression is controlledby a viral promoter. An example of such a virus is RV145 (Jones, T. R.,V. P. Muzithras, and Y. Oluzman. 1991. Replacement mutagenesis of thehuman cytomegalovirus genome: US10 and US11 gene products arenonessential. J. Virol. 65:5860-5872). Since it is under the control ofa viral promoter, beta-glucuronidase expression is an indirect indicatorof growth and replication of HCMV in this assay. At 96 hourspost-infection, the infected cell lysates are prepared (using 50 mMsodium phosphate [pH7.0] containing 0.1% Triton X-100 and 0.1% sarkosyl)and assayed for beta-glucuronidase activity using a substrate for theenzyme which when cleaved yields either a product which can be measuredcolorimetrically in a spectrophotometer or fluorescently in amicrofluorimeter. Examples of such substrates arep-nitrophenyl-beta-D-glucuronide and methylumbelliferylglucuronide,respectively. The presence of an antiviral compound is indicated by thereduced expression of the HCMV genome resident beta-glucuronidase gene,compared to the absence of inhibitor. Thus, the generation of thechromophore or fluorophore product in this assay is correspondinglyreduced.

Data from this assay generated using varying amounts of inhibitorcompound is also used to estimate the IC50 of an inhibitor compound.

HSV Antiviral (ELISA) Assay

Vero cells (ATCC #CCL-81) are plated on 96-well tissue culture plates at3.5×10⁴ cells per 100wp tissue culture DMEM (Dulbecco's modified Eaglemedia) supplemented with 2% fetal bovine serum (FBS) in each well. Afterovernight incubation @ 37° C. (in 5% CO₂) and 30 minutes prior toinfection with HSV-1 (multiplicity of infection equal to 0.006), cellsare either untreated, or treated with test compound (multipleconcentrations) or reference standard drug control. After approximately24 hours post-infection incubation @ 37° C. (in 5% CO₂), cells are fixedfor ELISA assay. The primary antibody is murine anti-HSV glycoprotein Dmonoclonal primary antibody and the secondary antibody is goatanti-mouse IgG linked to B-galactosidase. Thus the extent of viralreplication is determined by assessing 6-galactosidase activity byquantifying the generation of the 4-methyl umbelliferone fluorescentcleavage product after addition of the methylumbelliferyl-B-D-galactoside (Sigma #M1633) substrate on amicrofluorimeter (365nm for excitation and 450nm for emission).Antiviral activity (IC50) of the test compound is determined bycomparing the flourescence obtained in absence of compound to thatobtained in the presence of compound. Data is shown in Table I.

VZV Antiviral (ELISA) Assay

For the generation of stock VZV to be used in the assay, VZV strainEllen (ATCC #VR-1367 is used to infect human foreskin fibroblast (HFF)cells at low multiplicity (less than 0.1) and incubated overnight at 37°C. in 5% CO,. After the overnight incubation, the mixture of uninfectedand VZV-infected HFF infected cells are then harvested and added to eachwell of 96-well plates (3.5×10⁴ cells in 100 μl DMEM supplemented with2% FBS) which contain test compound or the reference standard drugcontrol (in 100 μl DMEM supplemented with 2% FBS per well). These cellsare incubated for three days at 37° C. in 5% CO₂, then fixed for ELISAassay. The primary antibody is murine anti-VZV glycoprotein IImonoclonal antibody (Applied Biosystems, Inc. #13-145-100) and thesecondary antibody is goat anti-mouse IgG linked to β-galactosidase.Thus the extent of viral replication is determined by assessingβ-galactosidase activity by quantifying the generation of the 4-methylumbelliferone fluorescent cleavage product after addition of the methylumbelliferyl-β-D-galactoside (Sigma #M1633) substrate on amicrofluorimeter (365 nm for excitation and 450 nm for emission).Antiviral activity (IC₅₀) of the test compound is determined bycomparing the flourescence obtained in absence of compound to thatobtained in the presence of compound. Data is shown in Table I.

TABLE 1 describes IC₅₀ data for compounds tested against herpes viruses.IC50 IC50 % inhibition IC50 (ug/ml) (ug/ml) 10 ug/ml (ug/ml) ExampleHCMV HSV VZV VZV 426 1.6 >10 2 1.8 427 0.8 >10 21 1.2 428 >10 >10 0 >10429 1 >10 0 >10 443 >10 >10 0 >10 444 4 8 0 >10 471 0.03 >10 27 >10 4807 >10 42 >10 483 5 1.2 45 >10 520 0.32 12 38 >10 525 0.018 2.5 39 >10593 >0.5 10 >10 608 >0.5 9 >10 609 1.5 8 >10 629 0.5 >10 >10632 >10 >10 >10 633 0.34 >10 >10 634 0.12 >10 >10 649 0.02 >10 0.5658 >0.5 10 659 >0.5 >10 660 >0.5 10 802 >10 >10 7.3 803 >10 >10 >7.5804 >10 >10 5.7 805 8 >10 1.6 1093 >10 >10 >10 1094 >10 >10 >7.5 10952.4 >10 7.1 1096 5.7 >10 6.7 1097 4 >10 5.50 1098 3.5 9 3.80 10995.6 >10 >7.5 1100 4.6 >10 7.3 1101 >10 >10 1

Thus, in accordance with the present invention, compounds of the presentinvention may be administered to a patient suffering from VZV, in anamount effective to inhibit the virus. Compounds of the presentinvention are thus useful to ameliorate to eliminate the symptoms of VZVinfections in mammals including, but not limited to humans.

Compounds of the invention may be administered to a patient either neator with a convention pharmaceutical carrier.

Applicable solid carriers can include one or more substances which mayalso act as flavoring agents, lubricants, solubilizers, suspendingagents, fillers, glidants, compression aids, binders ortablet-disintegrating agents or an encapsulating material. In powders,the carrier is a finely divided solid which is in admixture with thefinely divided active ingredient. In tablets, the active ingredient ismixed with a carrier having the necessary compression properties insuitable proportions and compacted in the shape and size desired. Thepowders and tablets preferably contain up to 99% of the activeingredient. Suitable solid carriers include, for example, calciumphosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch,gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Liquid carriers may be used in preparing solutions, suspensions,emulsions, syrups and elixirs. The active ingredient of this inventioncan be dissolved or suspended in a pharmaceutically acceptable liquidcarrier such as water, an organic solvent, a mixture of both orpharmaceutically acceptable oils or fat. The liquid carrier can containother suitable pharmaceutical additives such as solubilizers,emulsifiers, buffers, preservatives, sweeteners, flavoring agents,suspending agents, thickening agents, colors, viscosity regulators,stabilizers or osmo-regulators. Suitable examples of liquid carriers fororal and parenteral administration include water (particularlycontaining additives as above e.g. cellulose derivatives, preferablysodium carboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols e.g. glycols) and their derivatives,and oils (e.g. fractionated coconut oil and arachis oil). For parenteraladministration the carrier can also be an oily ester such as ethyloleate and isopropyl myristate. Sterile liquid carriers are used insterile liquid form compositions for parenteral administration.

Liquid pharmaceutical compositions which are sterile solutions orsuspensions can be utilized by, for example, intramuscular,intraperitoneal or subcutaneous injection. Sterile solutions can also beadministered intravenously. Oral administration may be either liquid orsolid composition form.

Preferably the pharmaceutical composition is in unit dosage form, e.g.as tablets or capsules. In such form, the composition is sub-divided inunit dose containing appropriate quantities of the active ingredient;the unit dosage forms can be packaged compositions, for example packetedpowders, vials, ampoules, prefilled syringes or sachets containingliquids. The unit dosage form can be, for example, a capsule or tabletitself, or it can be the appropriate number of any such compositions inpackage form.

The therapeutically effective dosage to be used in the treatment of CMVinfection must be subjectively determined by the attending physician.The variables involved include the the condition, age and weight of thepatient. The novel method of the invention for treating CMV infectioncomprises administering toa subject, including humans, an effectiveamount of at least one compound of Formula 1 or a non-toxic,pharmaceutically acceptable salt thereof. The compounds may beadministered orally, rectally, parenterally or topically to the skin andmucosa. The usual daily dose is depending on the specific compound,method of treatment and condition of the patient. The usual daily doseis 0.01-1000 mg/Kg for oral application, preferably 0.5-500 mg/Kg, and0.1-100 mg/Kg for parenteral application, preferably 0.5-50 mg/Kg.

What is claimed:
 1. A compound of the formula:

wherein A is pyridyl, imidazolyl, pyrolyl or indazolyl; R₁-R₁₂ areindependently hydrogen, alkyl of 1 to 4 carbon atoms, perhaloalkyl of 1to 4 carbon atoms, halogen, alkoxy of 1 to 4 carbon atoms, or cyano, orR₉ and R₁₀ or R₁₁ and R₁₂ may be taken together to form aryl of 5 to 7carbon atoms; W is O, NR₆, or is absent; G is aryl or heteroaryl; X is abond, —NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms,alkoxy of 1 to 6 carbon atoms, thioalkyl of 1 to 6 carbon atoms,alkylamino of 1 to 6 carbon atoms, or (CH)J; and J is alkyl of 1 to 6carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl or benzyl; and nis an integer from 1 to 6; or a pharmaceutically acceptable saltthereof.
 2. A compound of claim 1 wherein A is selected from pyridyl,imidazolyl, or pyrrolyl.
 3. A compound of claim 1 wherein A is3-pyridyl.
 4. A compound of claim 1 wherein A is substituted.
 5. Acompound of claim 1 wherein A is substituted with one or moresubstitutents selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perhaloalkyl of 1 to6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of3 to 10 carbon members, aryl, heteroaryl, halogen, —CN, —NO₂, —CO₂R₆,—COR₆, —OR₆, —SR₆, —SOR₆, —SO₂R₆, —CONR₇R₈, —NR₆N(R₇R₈), —N(R₇R₈), orW—Y—(CH₂)_(n)—Z wherein R₆ and R₇ are independently hydrogen, alkyl of 1to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, or aryl; R₈ ishydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbonatoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10members, aryl or heteroaryl, or R₇ and R₈, taken together may form a 3to 7 membered heterocycloalkyl; W is O, NR₆, or is absent; Y is —(CO)—or —(CO₂)—, or is absent; Z is alkyl of 1 to 4 carbon atoms, —CN,—CO₂R₆, COR₆, —CONR₇R₈, —OCOR₆, —NR₆COR₇, —OCONR₆, —OR₆, —SR₆, —SOR₆,—SO₂R₆, SR₆N(R₇R₈), —N(R₇R₈) or phenyl; and n is 1 to
 6. 6. A compoundof claim 1 wherein A is substituted with one or more substitutentsindependently selected from halogen or alkyl of 1 to 6 carbon atoms. 7.A compound of claim 1 wherein one or more of R₇-R₁₂ is independentlyselected from halogen, methyl, methoxy, and cyano.
 8. A compound ofclaim 1 wherein each of R₁-R₉ is hydrogen.
 9. A compound of claim 1wherein G is furyl or thiadiazole.
 10. A compound of claim 1 wherein Gis 1,2,3 thiadiazole.
 11. A compound of claim 1 wherein G is 2-furyl.12. A compound of claim 1 wherein X is a bond.
 13. A compound of claim 1wherein X is lower alkyl.
 14. A compound of claim 1 selected from:Furan-2-carboxylic acid [4-(3-pyridin-2-yl-thioureido)-phenyl]-amide;Furan-2-carboxylic acid [4-(3-pyridin-4-yl-thioureido)-phenyl]-amide;Furan-2-carboxylic acid [4-(3-pyridin-3-yl-thioureido)-phenyl]-amide;[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(6-chloro-pyridin-3-yl)-thioureido]-phenyl}-amide;[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(5-chloro-pyridin-3-yl)-thioureido]-phenyl}-amide;[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(5-bromo-pyridin-3-yl)-thioureido]-phenyl}-amide;[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(1-tert-butyl-1H-imidazol-2-yl)-thioureido]-phenyl}-amide;Furan-2-carboxylic acid(4-[3-(1-tert-butyl-1H-imidazol-2-yl)-thioureido]-phenyl}-amide;[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(5-trifluoromethyl-pyridin-3-yl)-thioureido]-phenyl}-amide;Furan-2-carboxylic acid[4-(3-pyridin-3-ylmethyl-thioureido)-phenyl]-amide;[1,2,3]Thiadiazole-4-carboxylic acid[4-(3-pyridin-3-ylmethyl-thioureido)-phenyl]-amide; Furan-2-carboxylicacid [4-(3-pyridin-4-ylmethyl-thioureido)-phenyl]-amide;[1,2,3]Thiadiazole-4-carboxylic acid[4-(3-pyridin-4-ylmethyl-thioureido)-phenyl]-amide;2-Fluoro-N-[4-(3-pyridin-3-yl-thioureido)-phenyl]-benzamide;2-Fluoro-N-[4-(3-pyridin-2-yl-thioureido)-phenyl]-benzamide;2-Fluoro-N-[4-(3-pyridin-4-yl-thioureido)-phenyl]-benzamide;2-Fluoro-N-[4-(3-pyridin-3-ylmethyl-thioureido)-phenyl]-benzamide;2-Fluoro-N-{4-[3-(1H-indazol-5-yl)-thioureido]-phenyl}-benzamide;N-{4-[3-(1-tert-Butyl-1H-imidazol-2-yl)-thioureido]-phenyl}-2-fluoro-benzamide;2-Fluoro-N-[4-(3-pyridin-4-ylmethyl-thioureido)-phenyl]-benzamide;2-Fluoro-N-{4-[3-(1-pyridin-4-yl-ethyl)-thioureido]-phenyl } -benzamide;and2-Fluoro-N-(4-{3-[1-(1-methyl-1H-pyrrol-2-yl)-ethyl]-thioureido}-phenyl)-benzamide;and pharmaceutically acceptable salts thereof.
 15. A pharmaceuticalcomposition comprising a compound of the formula:

wherein A is pyridyl, imidazolyl, pyrolyl, or indazolyl; R₁-R₁₂ areindependently hydrogen, alkyl of 1 to 4 carbon atoms, perhaloalkyl of 1to 4 carbon atoms, halogen, alkoxy of 1 to 4 carbon atoms, or cyano, orR₉ and R₁₀ or R₁₁ and R₁₂ may be taken together to form aryl of 5 to 7carbon atoms; W is O, NR₆, or is absent; G is aryl or heteroaryl; X is abond X is a bond, —NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6carbon atoms, alkoxy of 1 to 6 carbon atoms, or thioalkyl of 1 to 6carbon atoms, alkylamino of 1 to 6 carbon atoms, or (CH)J; and J isalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenylor benzyl, or a pharmaceutically acceptable salt thereof; and n is aninteger from 1 to 6; and a pharmaceutically acceptable carrier ordiluent.
 16. A method of inhibiting the replication of a herpes viruscomprising contacting a compound of the formula:

wherein A is pyridyl, imidazolyl, pyrolyl or indazolyl; R₉-R₁₂ areindependently hydrogen, alkyl of 1 to 4 carbon atoms, perhaloalkyl of 1to 4 carbon atoms, halogen, alkoxy of 1 to 4 carbon atoms, or cyano, orR₉ and R₁₀ or R₁₁ and R₁₂ may be taken together to form aryl of 5 to 7carbon atoms; W is O, NR₆, or is absent; G is aryl or heteroaryl; X is abond X is a bond, —NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6carbon atoms, alkoxy of 1 to 6 carbon atoms, or thioalkyl of 1 to 6carbon atoms, alkylamino of 1 to 6 carbon atoms, or (CH)J; and J isalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenylor benzyl; and n is an integer from 1 to 6; or a pharmaceuticallyacceptable salt thereof, with a herpes virus.
 17. The method of claim 16wherein the herpes virus is human cytomegalovirus.
 18. The method ofclaim 16 wherein the herpes virus is herpes simplex virus.
 19. Themethod of claim 16 wherein the herpes virus is varicella zoster virus.20. A method of treating a patient suffering from a herpes virusinfection comprising administering to the patient a therapeuticallyeffective amount of a compound having the formula:

wherein A is pyridyl, imidazolyl, pyrolyl or indazolyl; R₁-R₁₂ areindependently hydrogen, alkyl of 1 to 4 carbon atoms, perhaloalkyl of 1to 4 carbon atoms, halogen, alkoxy of 1 to 4 carbon atoms, or cyano, orR₉ and R₁₀ or R₁₁ and R₁₂ may be taken together to form aryl of 5 to 7carbon atoms; W is O, NR₆, or is absent; G is aryl or heteroaryl; X is abond X is a bond, —NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6carbon atoms, alkoxy of 1 to 6 carbon atoms, thioalkyl of 1 to 6 carbonatoms, alkylamino of 1 to 6 carbon atoms, or (CH)J; and J is alkyl of 1to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl or benzyl;and n is an integer from 1 to 6; or a pharmaceutically acceptable saltthereof.
 21. The method of claim 20 wherein the herpes virus is humancytomegalovirus.
 22. The method of claim 20 wherein the herpes virus isherpes simplex virus.
 23. The method of claim 20 where the herpes virusis varicella zoster virus.